Richard Simpson

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• Smith, K. A., Zúñiga, T. M., Baker, F. L., Batatinha, H., Pedlar, C. R., Burgess, S. C., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2024). COVID-19 vaccination produces exercise-responsive SARS-CoV-2 specific T-cells regardless of infection history. Journal of sport and health science, 13(1), 99-107.
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  The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific T-cells and neutralizing antibodies (nAbs) during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.
• Baker, F. L., Zuniga, T. M., Smith, K. A., Batatinha, H., Kulangara, T., Seckeler, M., Burgess, S. C., Katsanis, E., & Simpson, R. (2023). Exercise mobilizes diverse antigen specific T-cells and elevates neutralizing antibodies in humans with natural immunity to SARS CoV-2. Brain, Behavior, and Immunity – Health.
• Baker, F. L., Zúñiga, T. M., Smith, K. A., Batatinha, H., Kulangara, T. S., Seckeler, M. D., Burgess, S. C., Katsanis, E., & Simpson, R. J. (2023). Exercise mobilizes diverse antigen specific T-cells and elevates neutralizing antibodies in humans with natural immunity to SARS CoV-2. Brain, behavior, & immunity - health, 28, 100600.
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  Epidemiological data suggest that physical activity protects against severe COVID-19 and improves clinical outcomes, but how exercise augments the SARS-CoV-2 viral immune response has yet to be elucidated. Here we determine the antigen-specific CD4 and CD8 T-cell and humoral immunity to exercise in non-vaccinated individuals with natural immunity to SARS CoV-2, using whole-blood SARS-CoV-2 peptide stimulation assays, IFN-γ ELISPOT assays, 8-color flow cytometry, deep T-cell receptor (TCR) β sequencing, and anti-RBD-1 neutralizing antibody serology. We found that acute exercise reliably mobilized (∼2.5-fold increase) highly functional SARS-CoV-2-specific T-cells to the blood compartment in those with natural immunity to the virus. The mobilized cells reacted with spike protein (including alpha (α) and delta (δ)-variants), membrane, and nucleocapsid peptides in those previously infected but not in controls. Both groups reliably mobilized T-cells reacting with Epstein-Barr viral peptides. Exercise mobilized SARS-CoV-2 specific T-cells maintained broad TCR-β diversity with no impact on CDR3 length or V and J family gene usage. Exercise predominantly mobilized MHC I restricted (i.e. CD8) SARS-CoV-2 specific T-cells that recognized ORF1ab, surface, ORF7b, nucleocapsid, and membrane proteins. SARS-CoV-2 neutralizing antibodies were transiently elevated ∼1.5-fold during exercise after infection. In conclusion, we provide novel data on a potential mechanism by which exercise could increase SARS-CoV-2 immunosurveillance via the mobilization and redistribution of antigen-specific CD8 T-cells and neutralizing antibodies. Further research is needed to define the tissue specific disease protective effects of exercise as SARS-CoV-2 continues to evolve, as well as the impact of COVID-19 vaccination on this response.
• Batatinha, H., Diak, D. M., Niemiro, G. M., Baker, F. L., Smith, K. A., Zúñiga, T. M., Mylabathula, P. L., Seckeler, M. D., Lau, B., LaVoy, E. C., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2023). Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice. Frontiers in immunology, 14, 1067369.
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  Every bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia.
• Batatinha, H., Diak, D., Niemiro, G., Baker, F. L., Smith, K. A., Zuniga, T. M., Seckeler, M., Lau, B., LaVoy, E., Gustafson, M., Katsanis, E., & Simpson, R. (2023). Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice. Frontiers in Immunology.
• Crane, J. C., Gordon, M. J., Basen-Engquist, K., Ferrajoli, A., Markofski, M. M., Lee, C. Y., Fares, S., Simpson, R. J., & LaVoy, E. C. (2023). Relationships between T-lymphocytes and physical function in adults with chronic lymphocytic leukemia: Results from the HEALTH4CLL pilot study. European journal of haematology, 110(6), 732-742.
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  Examine physical function and T-cell phenotype in patients with chronic lymphocytic leukemia (CLL) before and after a physical activity (PA) intervention.
• Fiuza-Luces, C., Valenzuela, P. L., Gálvez, B. G., Ramírez, M., López-Soto, A., Simpson, R. J., & Lucia, A. (2023). The effect of physical exercise on anticancer immunity. Nature reviews. Immunology.
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  Regular physical activity is associated with lower cancer incidence and mortality, as well as with a lower rate of tumour recurrence. The epidemiological evidence is supported by preclinical studies in animal models showing that regular exercise delays the progression of cancer, including highly aggressive malignancies. Although the mechanisms underlying the antitumorigenic effects of exercise remain to be defined, an improvement in cancer immunosurveillance is likely important, with different immune cell subtypes stimulated by exercise to infiltrate tumours. There is also evidence that immune cells from blood collected after an exercise bout could be used as adoptive cell therapy for cancer. In this Perspective, we address the importance of muscular activity for maintaining a healthy immune system and discuss the effects of a single bout of exercise (that is, 'acute' exercise) and those of 'regular' exercise (that is, repeated bouts) on anticancer immunity, including tumour infiltrates. We also address the postulated mechanisms and the clinical implications of this emerging area of research.
• Gilman, K. E., Matiatos, A. P., Cracchiolo, M. J., Moon, A. G., Davini, D. W., Simpson, R. J., & Katsanis, E. (2023). Multiagent Intratumoral Immunotherapy Can Be Effective in A20 Lymphoma Clearance and Generation of Systemic T Cell Immunity. Cancers, 15(7).
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  The use of immunotherapies has shown promise against selective human cancers. Identifying novel combinations of innate and adaptive immune cell-activating agents that can work synergistically to suppress tumor growth and provide additional protection against resistance or recurrence is critical. The A20 murine lymphoma model was used to evaluate the effect of various combination immunotherapies administered intratumorally. We show that single-modality treatment with Poly(I:C) or GM-CSF-secreting allogeneic cells only modestly controls tumor growth, whereas when given together there is an improved benefit, with 50% of animals clearing tumors and surviving long-term. Neither heat nor irradiation of GM-CSF-secreting cells enhanced the response over use of live cells. The use of a TIM-3 inhibitory antibody and an OX40 agonist in combination with Poly(I:C) allowed for improved tumor control, with 90% of animals clearing tumors with or without a combination of GM-CSF-secreting cells. Across all treatment groups, mice rejecting their primary A20 tumors were immune to subsequent challenge with A20, and this longstanding immunity was T-cell dependent. The results herein support the use of combinations of innate and adaptive immune activating agents for immunotherapy against lymphoma and should be investigated in other cancer types.
• Zuniga, T. M., Baker, F. L., Lau, B., Gustafson, M. P., Katsanis, E., & Simpson, R. (2023). Clonal kinetics and single-cell transcriptional profiles of T-cells mobilized to blood by acute exercise. Medicine & Science in Sports & Exercise.
• Zúñiga, T. M., Baker, F. L., Smith, K. A., Batatinha, H., Lau, B., Burgess, S. C., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2023). Clonal Kinetics and Single-Cell Transcriptional Profiles of T Cells Mobilized to Blood by Acute Exercise. Medicine and science in sports and exercise, 55(6), 991-1002.
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  Acute exercise redistributes large numbers of memory T cells, which may contribute to enhanced immune surveillance in regular exercisers. It is not known, however, if acute exercise promotes a broad or oligoclonal T-cell receptor (TCR) repertoire or evokes transcriptomic changes in "exercise-responsive" T-cell clones.
• Batatinha, H., & Simpson, R. J. (2022). Reply to Ewell and Abbotts. Journal of applied physiology (Bethesda, Md. : 1985), 133(1), 168-169.
• Batatinha, H., Baker, F. L., Smith, K. A., Zúñiga, T. M., Pedlar, C. R., Burgess, S. C., Katsanis, E., & Simpson, R. J. (2022). Recent COVID-19 vaccination has minimal effects on the physiological responses to graded exercise in physically active healthy people. Journal of applied physiology (Bethesda, Md. : 1985), 132(2), 275-282.
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  Athletes are advised to receive the COVID-19 vaccination to protect themselves from SARS-CoV-2 infection during major competitions. Despite this, many athletes are reluctant to get the COVID-19 vaccine due to concerns that symptoms of vaccinosis may impair athletic performance. This study aimed to determine the effects of COVID-19 vaccination on the physiological responses to graded exercise. Healthy physically active participants completed a 20-min bout of graded cycling exercise at intensities corresponding to 50%, 60%, 70%, and 80% of the predetermined V̇O before and ∼21 days after receiving the COVID-19 vaccine (2-dose Pfizer mRNA or 1-dose Johnson & Johnson). Vaccination had no effect on a large number of physiological responses to exercise measured in blood (e.g., lactate, epinephrine, and cortisol) and by respiratory gas exchange (e.g., oxygen uptake, CO production, ventilation, respiratory exchange ratio, predicted V̇O, and ventilatory threshold) ( > 0.05). We did, however, find significant elevations in heart rate (∼5 beats/min) and norepinephrine ( = 0.006 and 0.04, respectively) in response to vigorous (i.e., 70%-80% V̇O) intensity exercise after vaccination, particularly in those who received the two-shot Pfizer mRNA vaccine regimen. These findings held true when compared with demographically matched controls who completed identical bouts of exercise several weeks apart without receiving a vaccine; delta values for heart rate ( = 0.03) and norepinephrine ( = 0.01) were elevated in the second trial for those who received the Pfizer mRNA vaccine compared with the controls at the 70% and 80% V̇O stages, respectively. Recent COVID-19 vaccination has minimal effects on the physiological responses to graded exercise in physically active healthy people. The small elevations in cardiovascular and neuroendocrine responses to exercise after the Pfizer mRNA vaccine regimen could have implications for athletes at the elite level and warrants investigation. Recent COVID-19 vaccination does not affect a large number of physiological responses to graded exercise, indicating that vaccination is unlikely to impair exercise capacity in normal healthy people. Heart rate and norepinephrine levels were elevated in response to exercise after the two-dose Pfizer mRNA vaccination compared to controls. Small elevations in cardiovascular and neuroendocrine responses to exercise after recent COVID-19 vaccination could have implications for exercise performance in elite athletes and warrants investigation.
• Gilman, K. E., Cracchiolo, M. J., Matiatos, A. P., Davini, D. W., Simpson, R. J., & Katsanis, E. (2022). Partially replacing cyclophosphamide with bendamustine in combination with cyclosporine A improves survival and reduces xenogeneic graft-versus-host-disease. Frontiers in immunology, 13, 1045710.
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  The use of allogeneic hematopoietic cell transplantation (allo-HCT) for treating hematological disorders is increasing, but the development of graft-versus-host disease (GvHD) remains a major cause of morbidity and mortality. The use of post-transplant cyclophosphamide (CY) has significantly improved outcomes following allo-HCT, but complications of viral reactivation due to delayed immune reconstitution or relapse remain. Other laboratories are evaluating the potential benefit of lowering the dose of CY given post-transplant, whereas our laboratory has been focusing on whether partially replacing CY with another DNA alkylating agent, bendamustine (BEN) may be advantageous in improving outcomes with allo-HCT.
• Katsanis, E., Hanley, P. J., & Simpson, R. J. (2022). Editorial: Advances in Pediatric Hematopoietic Cell Therapies and Transplantation. Frontiers in pediatrics, 10, 847288.
• Katsanis, E., Stea, B., Kovacs, K., Truscott, L., Husnain, M., Khurana, S., Roe, D. J., & Simpson, R. J. (2022). Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. Transplantation and cellular therapy, 28(7), 390.e1-390.e10.
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  Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.
• Molina, M. S., Hoffman, E. A., Stokes, J., Kummet, N., Simpson, R. J., & Katsanis, E. (2022). Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway. PloS one, 17(8), e0273075.
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  The immediate precursor to murine type 1 conventional DCs (cDC1s) has recently been established and named "pre-cDC1s". Mature CD8α+ cDC1s are recognized for suppressing graft-versus-host disease (GvHD) while promoting graft-versus-leukemia (GvL), however pre-cDC1s have not previously been investigated in the context of alloreactivity or anti-tumor responses. Characterization of pre-cDC1s, compared to CD8α+ cDC1s, found that a lower percentage of pre-cDC1s express PD-L1, yet express greater PD-L1 by MFI and a greater percent PIR-B, a GvHD-suppressing molecule. Functional assays were performed ex vivo following in vivo depletion of CD8α+ DCs to examine whether pre-cDC1s play a redundant role in alloreactivity. Proliferation assays revealed less allogeneic T-cell proliferation in the absence of CD8α+ cDC1s, with slightly greater CD8+ T-cell proliferation. Further, in the absence of CD8α+ cDC1s, stimulated CD8+ T-cells exhibited significantly less PD-1 expression compared to CD4+ T-cells, and alloreactive T-cell death was significantly lower, driven by reduced CD4+ T-cell death. Tumor-killing assays revealed that T-cells primed with CD8α-depleted DCs ex vivo induce greater killing of A20 B-cell leukemia cells, particularly when antigen (Ag) is limited. Bulk RNA sequencing revealed distinct transcriptional programs of these DCs, with pre-cDC1s exhibiting activated PD-1/PD-L1 signaling compared to CD8α+ cDC1s. These results indicate distinct T-cell-priming capabilities of murine pre-cDC1s compared to CD8α+ cDC1s ex vivo, with potentially clinically relevant implications in suppressing GvHD while promoting GvL responses, highlighting the need for greater investigation of murine pre-cDC1s.
• Mylabathula, P. L., Diak, D. M., Baker, F. L., Niemiro, G. M., Markofski, M. M., Crucian, B. E., Katsanis, E., & Simpson, R. J. (2022). IL-2 and Zoledronic Acid Therapy Restores the Anti-Leukemic Activity of Human Lymphocytes Pre-Exposed to Simulated Microgravity. Frontiers in bioscience (Landmark edition), 27(7), 215.
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  We have previously shown that the anti-tumor activity of human lymphocytes is diminished after 12-hours pre-exposure to simulated microgravity (SMG). Here we used an immunocompromised mouse model to determine if this loss of function would extend , and to also test the efficacy of IL-2 and zoledronic acid (ZOL) therapy as a potential countermeasure against SMG-induced immune dysfunction. We adoptively transferred human lymphocytes that were exposed to either SMG or 1G-control into NSG-Tg (Hu-IL15) mice 1-week after they were injected with a luciferase-tagged human chronic myeloid leukemia (K562) cell line. Tumor growth was monitored 2x weekly with bioluminescence imaging (BLI) for up to 6-weeks.
• Niemiro, G. M., Coletta, A. M., Agha, N. H., Mylabathula, P. L., Baker, F. L., Brewster, A. M., Bevers, T. B., Fuentes-Mattei, E., Basen-Engquist, K., Katsanis, E., Gilchrist, S. C., & Simpson, R. J. (2022). Correction: Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial. Immunity & ageing : I & A, 19(1), 30.
• Niemiro, G. M., Coletta, A. M., Agha, N. H., Mylabathula, P. L., Baker, F. L., Brewster, A. M., Bevers, T. B., Fuentes-Mattei, E., Basen-Engquist, K., Katsanis, E., Gilchrist, S. C., & Simpson, R. J. (2022). Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial. Immunity & ageing : I & A, 19(1), 17.
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  Immunosenescence is described as age-associated changes within the immune system that are responsible for decreased immunity and increased cancer risk. Physically active individuals have fewer 'senescent' and more naïve T-cells compared to their sedentary counterparts, but it is not known if exercise training can rejuvenate 'older looking' T-cell profiles. We determined the effects of 12-weeks supervised exercise training on the frequency of T-cell subtypes in peripheral blood and their relationships with circulating levels of the muscle-derived cytokines (i.e. 'myokines') IL-6, IL-7, IL-15 and osteonectin in older women at high risk of breast cancer. The intervention involved 3 sessions/week of either high intensity interval exercise (HIIT) or moderate intensity continuous exercise (MICT) and were compared to an untrained control (UC) group.
• Rosa-Neto, J. C., Lira, F. S., Little, J. P., Landells, G., Islam, H., Chazaud, B., Pyne, D. B., Teixeira, A. M., Batatinha, H., Moura Antunes, B., Guerra Minuzzi, L., Palmowski, J., Simpson, R. J., & Krüger, K. (2022). Immunometabolism-fit: How exercise and training can modify T cell and macrophage metabolism in health and disease. Exercise immunology review, 28, 29-46.
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  The term immunometabolism describes cellular and molecular metabolic processes that control the immune system and the associated immune responses. Acute exercise and regular physical activity have a substantial influence on the metabolism and the immune system, so that both processes are closely associated and influence each other bidirectionally.
• Stokes, J., Simpson, R. J., & Katsanis, E. (2022). Commentary: Post-Transplantation Cyclophosphamide Uniquely Restrains Alloreactive CD4+ T-Cell Proliferation and Differentiation After Murine MHC-Haploidentical Hematopoietic Cell Transplantation. Frontiers in immunology, 13, 887648.
• Valenzuela, P. L., Saco-Ledo, G., Santos-Lozano, A., Morales, J. S., Castillo-García, A., Simpson, R. J., Lucia, A., & Fiuza-Luces, C. (2022). Exercise Training and Natural Killer Cells in Cancer Survivors: Current Evidence and Research Gaps Based on a Systematic Review and Meta-analysis. Sports medicine - open, 8(1), 36.
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  Exercise training can positively impact the immune system and particularly natural killer (NK) cells, at least in healthy people. This effect would be of relevance in the context of cancer given the prominent role of these cells in antitumor immunity. In this systematic review and meta-analysis, we aimed to summarize current evidence on the effects of exercise training on the levels and function of NK cells in cancer survivors (i.e., from the time of diagnosis until the end of life).
• Zúñiga, T. M., Baker, F. L., Smith, K. A., Batatinha, H., Lau, B., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2022). Acute exercise mobilizes NKT-like cells with a cytotoxic transcriptomic profile but does not augment the potency of cytokine-induced killer (CIK) cells. Frontiers in immunology, 13, 938106.
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  CD3/CD56 Natural killer (NK) cell-like T-cells (NKT-like cells) represent
• Alfano, C. A., Bower, J. L., Connaboy, C., Agha, N. H., Baker, F. L., Smith, K. A., So, C. J., & Simpson, R. J. (2021). Mental health, physical symptoms and biomarkers of stress during prolonged exposure to Antarctica's extreme environment. Acta Astronautica.
• Azadan, R. J., Agha, N. H., Kunz, H. E., Baker, F. L., Mylabathula, P. L., Ledoux, T. A., O'Connor, D. P., Pedlar, C. R., & Simpson, R. J. (2021). The effects of normoxic endurance exercise on erythropoietin (EPO) production and the impact of selective β and non-selective β + β adrenergic receptor blockade. European journal of applied physiology, 121(5), 1499-1511.
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  Habitual endurance exercise results in increased erythropoiesis, which is primarily controlled by erythropoietin (EPO), yet studies demonstrating upregulation of EPO via a single bout of endurance exercise have been equivocal. This study compares the acute EPO response to 30 min of high versus 90 min of moderate-intensity endurance exercise and whether that response can be upregulated via selective adrenergic receptor blockade.
• Baker, F. L., & Simpson, R. J. (2021). Exercise to Support Optimal Immune Function. ACSM's Health & Fitness Journal, 25(1), 5--8.
• Baker, F. L., Smith, K. A., Zúñiga, T. M., Batatinha, H., Niemiro, G. M., Pedlar, C. R., Burgess, S. C., Katsanis, E., & Simpson, R. J. (2021). Acute exercise increases immune responses to SARS CoV-2 in a previously infected man. Brain, behavior, & immunity - health, 18, 100343.
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  Evidence is emerging that exercise and physical activity provides protection against severe COVID-19 disease in patients infected with SARS-CoV-2, but it is not known how exercise affects immune responses to the virus. A healthy man completed a graded cycling ergometer test prior to and after SARS-CoV-2 infection, then again after receiving an adenovirus vector-based COVID-19 vaccine. Using whole blood SARS-CoV-2 peptide stimulation assays, IFN-γ ELISPOT assays, flow cytometry, viral-specific T-cell expansion assays and deep T-cell receptor (TCR) β sequencing, we found that exercise robustly mobilized highly functional SARS-CoV-2 specific T-cells to the blood compartment that recognized spike protein, membrane protein, nucleocapsid antigen and the B.1.1.7 α-variant, and consisted mostly of CD3+/CD8+ T-cells and double-negative (CD4-/CD8-) CD3 T-cells. The magnitude of SARS-CoV-2 T-cell mobilization with exercise was intensity dependent and robust when compared to T-cells recognizing other viruses (e.g. CMV, EBV, influenza). Vaccination enhanced the number of exercise-mobilized SARS-CoV-2 T-cells recognizing spike protein and the α-variant only. Exercise-mobilized SARS-CoV-2 specific T-cells proliferated more vigorously to peptide stimulation and maintained broad TCR-β diversity against SARS-CoV-2 antigens both before and after expansion. Neutralizing antibodies to SARS-CoV-2 were transiently elevated during exercise after both infection and vaccination. Finally, infection was associated with an increased metabolic demand to defined exercise workloads, which was restored to pre-infection levels after vaccination. This case study provides impetus for larger studies to determine if these immune responses to exercise can facilitate viral clearance, ameliorate symptoms of long COVID syndrome, and/or restore functional exercise capacity following SARS-CoV-2 infection.
• Bruinvels, G., Lewis, N. A., Blagrove, R. C., Scott, D., Simpson, R. J., Baggish, A. L., Rogers, J. P., Ackerman, K. E., & Pedlar, C. R. (2021). COVID-19-Considerations for the Female Athlete. Frontiers in sports and active living, 3, 606799.
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  The SARS CoV-2 virus (COVID-19) caused the whole sporting calendar to be paused. As we embark on the challenge of navigating through the return to play (RTP) process, there is a necessity to consider the needs of all athletes. This commentary specifically considers recommendations and requirements for the female athlete with a physiological emphasis during and following the COVID-19 pandemic, however, it will be relevant for any similar future scenarios that may present. It is important to acknowledge that there remain many unknowns surrounding COVID-19 and the female athlete both in the short- and long-term.
• Coletta, A. M., Agha, N. H., Baker, F. L., Niemiro, G. M., Mylabathula, P. L., Brewster, A. M., Bevers, T. B., Fuentes-Mattei, E., Basen-Engquist, K., Gilchrist, S. C., & Simpson, R. J. (2021). The impact of high-intensity interval exercise training on NK-cell function and circulating myokines for breast cancer prevention among women at high risk for breast cancer. Breast cancer research and treatment.
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  Preclinical evidence suggests that natural killer cell (NK-cell) function and myokines facilitate the protective effects of exercise for breast cancer prevention. Since higher-intensity exercise acutely promotes greater mobilization and larger changes in NK-cell cytotoxicity than lower-intensity, high-intensity interval training (HIIT) might offer increased immune protection compared to moderate-intensity continuous-training (MICT). This study compared a 12-week HIIT program to a 12-week MICT program and usual care on changes in resting NK-cell function and circulating myokines among women at high risk for breast cancer.
• Elzayat, M. T., Markofski, M. M., Simpson, R. J., Laughlin, M., & LaVoy, E. C. (2021). No Effect of Acute Eccentric Resistance Exercise on Immune Responses to Influenza Vaccination in Older Adults: A Randomized Control Trial. Frontiers in physiology, 12, 713183.
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  Older adults are at elevated risk for morbidity and mortality caused by influenza. Vaccination is the primary means of prophylaxis, but protection is often compromised in older adults. As resistance exercise mobilizes immune cells into muscle, it may enhance vaccination response.
• Gustafson, M. P., Wheatley-Guy, C. M., Rosenthal, A. C., Gastineau, D. A., Katsanis, E., Johnson, B. D., & Simpson, R. J. (2021). Exercise and the immune system: taking steps to improve responses to cancer immunotherapy. Journal for immunotherapy of cancer, 9(7).
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  The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.
• Krieger, S. S., Zwart, S. R., Mehta, S., Wu, H., Simpson, R. J., Smith, S. M., & Crucian, B. (2021). Alterations in Saliva and Plasma Cytokine Concentrations During Long-Duration Spaceflight. Frontiers in immunology, 12, 725748.
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  Long-duration spaceflight is known to cause immune dysregulation in astronauts. Biomarkers of immune system function are needed to determine both the need for and effectiveness of potential immune countermeasures for astronauts. Whereas plasma cytokine concentrations are a well-established biomarker of immune status, salivary cytokine concentrations are emerging as a sensitive indicator of stress and inflammation. For this study, to aid in characterizing immune dysregulation during spaceflight, plasma and saliva cytokines were monitored in astronauts before, during and after long-duration spaceflight onboard the International Space Station. Blood was collected from 13 astronauts at 3 timepoints before, 5 timepoints during and 3 timepoints after spaceflight. Saliva was collected from 6 astronauts at 2 timepoints before spaceflight, 2 timepoints during and 3 timepoints following spaceflight. Samples were analyzed using multiplex array technology. Significant increases in the plasma concentration of IL-3, IL-15, IL-12p40, IFN-α2, and IL-7 were observed during spaceflight compared to before flight baseline. Significant decreases in saliva GM-CSF, IL-12p70, IL-10 and IL-13 were also observed during spaceflight as compared to compared to before flight baseline concentrations. Additionally, plasma TGFβ1 and TGFβ2 concentrations tended to be consistently higher during spaceflight, although these did not reach statistical significance. Overall, the findings confirm an hormonal dysregulation of immunity, appearing pro-inflammatory and Th1 in nature, persists during long-duration orbital spaceflight. These biomarkers may therefore have utility for monitoring the effectiveness of biomedical countermeasures for astronauts, with potential application in terrestrial research and medicine.
• Molina, M. S., Hoffman, E. A., Stokes, J., Kummet, N., Smith, K. A., Baker, F., Zúñiga, T. M., Simpson, R. J., & Katsanis, E. (2021). Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death. Frontiers in immunology, 12, 699128.
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  The growth factor Flt3 ligand (Flt3L) is central to dendritic cell (DC) homeostasis and development, controlling survival and expansion by binding to Flt3 receptor tyrosine kinase on the surface of DCs. In the context of hematopoietic cell transplantation, Flt3L has been found to suppress graft-versus-host disease (GvHD), specifically host DCs. We previously reported that the pre-transplant conditioning regimen consisting of bendamustine (BEN) and total body irradiation (TBI) results in significantly reduced GvHD compared to cyclophosphamide (CY)+TBI. Pre-transplant BEN+TBI conditioning was also associated with greater Flt3 expression among host DCs and an accumulation of pre-cDC1s. Here, we demonstrate that exposure to BEN increases Flt3 expression on both murine bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs). BEN favors development of murine plasmacytoid DCs, pre-cDC1s, and cDC2s. While humans do not have an identifiable equivalent to murine pre-cDC1s, exposure to BEN resulted in decreased plasmacytoid DCs and increased cDC2s. BEN exposure and heightened Flt3 signaling are associated with a distinct regulatory phenotype, with increased PD-L1 expression and decreased ICOS-L expression. BMDCs exposed to BEN exhibit diminished pro-inflammatory cytokine response to LPS and induce robust proliferation of alloreactive T-cells. These proliferative alloreactive T-cells expressed greater levels of PD-1 and underwent increased programmed cell death as the concentration of BEN exposure increased. Alloreactive CD4 T-cell death may be attributable to pre-cDC1s and provides a potential mechanism by which BEN+TBI conditioning limits GvHD and yields T-cells tolerant to host antigen.
• Simpson, R. J., & Pawelec, G. (2021). Is mechanical loading essential for exercise to preserve the aging immune system?. Immunity & ageing : I & A, 18(1), 26.
• Simpson, R. J., Boßlau, T. K., Weyh, C., Niemiro, G. M., Batatinha, H., Smith, K. A., & Krüger, K. (2021). Exercise and adrenergic regulation of immunity. Brain, behavior, and immunity, 97, 303-318.
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  Exercise training has a profound impact on immunity, exerting a multitude of positive effects in indications such as immunosenescence, cancer, viral infections and inflammatory diseases. The immune, endocrine and central nervous systems work in a highly synergistic manner and it has become apparent that catecholamine signaling through leukocyte β-adrenergic receptors (β-ARs) is a key mechanism by which exercise mediates improvements in immune function to help mitigate numerous disease conditions. Central to this is the preferential mobilization and redistribution of effector lymphocytes with potent anti-viral and anti-tumor activity, their interaction with muscle-derived cytokines, and the effects of catecholamine signaling on mitochondrial biogenesis, immunometabolism and the resulting inflammatory response. Here, we review the impact of acute and chronic exercise on adrenergic regulation of immunity in the context of aging, cancer, viral infections and inflammatory disease. We also put forth our contention that exercise interventions designed to improve immunity, prevent disease and reduce inflammation should consider the catecholamine-AR signaling axis as a therapeutic target and ask whether or not the adrenergic signaling machinery can be 'trained' to improve immune responses to stress, disease or during the normal physiological process of aging. Finally, we discuss potential strategies to augment leukocyte catecholamine signaling to boost the effects of exercise on immunity in individuals with desensitized β-ARs or limited exercise tolerance.
• Stanley, K., Hanmod, S., Simpson, R. J., & Katsanis, E. (2021). Haploidentical hematopoietic cell transplantation is even more advantageous during the COVID-19 pandemic. Pediatric transplantation, 25(3), e14004.
• Stokes, J., Molina, M. S., Hoffman, E. A., Simpson, R. J., & Katsanis, E. (2021). Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. Cancers, 13(7).
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  Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
• Valenzuela, P. L., Simpson, R. J., Castillo-García, A., & Lucia, A. (2021). Physical activity: A coadjuvant treatment to COVID-19 vaccination?. Brain, behavior, and immunity, 94, 1-3.
• Agha, N. H., Baker, F. L., Kunz, H. E., Spielmann, G., Mylabathula, P. L., Rooney, B. V., Mehta, S. K., Pierson, D. L., Laughlin, M. S., Markofski, M. M., & others, . (2020). Salivary antimicrobial proteins and stress biomarkers are elevated during a 6-month mission to the International Space Station. Journal of Applied Physiology, 128(2), 264--275.
• Agha, N. H., Mehta, S. K., Rooney, B. V., Laughlin, M. S., Markofski, M. M., Pierson, D. L., Katsanis, E., Crucian, B. E., & Simpson, R. J. (2020). Exercise as a countermeasure for latent viral reactivation during long duration space flight. FASEB journal : official publication of the Federation of American Societies for Experimental Biology.
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  Latent viral reactivation is a commonly reported manifestation of immune system dysregulation during spaceflight. As physical fitness and exercise training have been shown to benefit multiple arms of the immune system, we hypothesized that higher levels of preflight physical fitness and/or maintaining fitness during a mission would protect astronauts from latent viral reactivation. Standardized tests of maximal strength, muscular endurance, flexibility, and cardiorespiratory fitness (CRF) were performed in 22 international space station (ISS) crewmembers before and after a ~6-month mission. Reactivation of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella zoster virus (VZV) was determined in crewmembers and ground-based controls before, during, and after spaceflight. Crewmembers with higher CRF before spaceflight had a 29% reduced risk of latent viral reactivation compared to crew with lower CRF. Higher preflight upper body muscular endurance was associated with a 39% reduced risk of viral reactivation, a longer time to viral reactivation, and lower peak viral DNA concentrations, particularly for EBV and VZV. Latent viral reactivation rates were highest in crew with lower preflight CRF and higher levels of CRF deconditioning on return to Earth. We conclude that physical fitness may protect astronauts from latent viral reactivation during long duration spaceflight missions.
• Azadan, R. J., Agha, N. H., Kunz, H. E., Baker, F. L., Mylabathula, P. L., Ledoux, T. A., O'Connor, D. P., Pedlar, C., & Simpson, R. J. (2020). The effects of normoxic endurance exercise on erythropoietin (EPO) production and the impact of selective $beta$1 and non-selective $beta$1+ $beta$2 adrenergic receptor blockade. European Journal of Applied Physiology.
• Baker, F. L., Bigley, A. B., Agha, N. H., Pedlar, C. R., O'Connor, D. P., Bond, R. A., Bollard, C. M., Katsanis, E., & Simpson, R. J. (2020). Systemic β-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells. Frontiers in Immunology, 10, 3082.
• Bruinvels, G., Lewis, N., Blagrove, R., Scott, D., Simpson, R., Baggish, A., Rogers, J., Ackerman, K., & Pedlar, C. (2020). COVID-19-Considerations for the female athlete.
• Connaboy, C., LaGoy, A. D., Johnson, C. D., Sinnott, A. M., Eagle, S. R., Bower, J. L., Pepping, G., Simpson, R. J., & Alfano, C. A. (2020). Sleep deprivation impairs affordance perception behavior during an action boundary accuracy assessment. Acta Astronautica, 166, 270--276.
• Connaboy, C., Sinnott, A. M., LaGoy, A. D., Krajewski, K. T., Johnson, C. D., Pepping, G., Simpson, R. J., Bower, J. L., & Alfano, C. A. (2020). Cognitive performance during prolonged periods in isolated, confined, and extreme environments. Acta Astronautica, 177, 545--551.
• Crucian, B. E., Makedonas, G., Sams, C. F., Pierson, D. L., Simpson, R., Stowe, R. P., Smith, S. M., Zwart, S. R., Krieger, S. S., Rooney, B., & others, . (2020). Countermeasures-based Improvements in Stress, Immune System Dysregulation and Latent Herpesvirus Reactivation onboard the International Space Station--Relevance for Deep Space Missions and Terrestrial Medicine. Neuroscience & Biobehavioral Reviews.
• Elzayat, M. T., Markofski, M. M., Simpson, R. J., Laughlin, M., & LaVoy, E. C. (2020). No effect of resistance exercise on antibody responses to influenza vaccination in older adults: a randomized control trial. medRxiv.
• Katsanis, E., Maher, K., Roe, D. J., & Simpson, R. J. (2020). Progressive substitution of posttransplant cyclophosphamide with bendamustine: A phase I study in haploidentical bone marrow transplantation. eJHaem, 1(1), 286--292.
• Krajewski, K. T., Dever, D. E., Johnson, C. C., Mi, Q. i., Simpson, R. J., Graham, S. M., Moir, G. L., Ahamed, N. U., Flanagan, S. D., Anderst, W. J., & others, . (2020). Load Magnitude and Locomotion Pattern Alter Locomotor System Function in Healthy Young Adult Women. Frontiers in Bioengineering and Biotechnology, 8, 1066.
• Krajewski, K. T., Dever, D. E., Johnson, C. C., Mi, Q., Simpson, R. J., Graham, S. M., Moir, G. L., Ahamed, N. U., Flanagan, S. D., Anderst, W. J., & Connaboy, C. (2020). Load Magnitude and Locomotion Pattern Alter Locomotor System Function in Healthy Young Adult Women. Frontiers in bioengineering and biotechnology, 8, 582219.
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  During cyclical steady state ambulation, such as walking, variability in stride intervals can indicate the state of the system. In order to define locomotor system function, observed variability in motor patterns, stride regulation and gait complexity must be assessed in the presence of a perturbation. Common perturbations, especially for military populations, are load carriage and an imposed locomotion pattern known as forced marching (FM). We examined the interactive effects of load magnitude and locomotion pattern on motor variability, stride regulation and gait complexity during bipedal ambulation in recruit-aged females.
• Kunz, H. E., Agha, N. H., Hussain, M., LaVoy, E. C., Smith, K. A., Mylabathula, P., Diak, D., Baker, F. L., O'Connor, D. P., Bond, R. A., Katsanis, E., Bollard, C. M., & Simpson, R. J. (2020). The effects of β and β adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise. Cell stress & chaperones, 25(6), 993-1012.
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  The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β AR antagonist (nadolol) or a β AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3 T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β AR mediated, thus highlighting a role for the β AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.
• Kunz, H., Quiriarte, H., Simpson, R. J., Ploutz-Snyder, R., McMonigal, K., Sams, C., & Crucian, B. (2020). Stable red blood cell concentrations seen in astronauts on long space missions.
• LaGoy, A. D., Sinnott, A. M., Ambarian, M., Pepping, G., Simpson, R. J., Agha, N. H., Bower, J. L., Alfano, C. A., & Connaboy, C. (2020). Differences in affordance-based behaviors within an isolated and confined environment are related to sleep, emotional health and physiological parameters. Acta Astronautica, 176, 238--246.
• Molina, M. S., Stokes, J., Hoffman, E. A., Eremija, J., Zeng, Y., Simpson, R. J., & Katsanis, E. (2020). Bendamustine Conditioning Skews Murine Host DCs Toward Pre-cDC1s and Reduces GvHD Independently of Batf3. Frontiers in immunology, 11, 1410.
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  Graft-versus-host disease (GvHD) remains the second leading cause of death in allogeneic hematopoietic stem cell transplantation recipients, highlighting the need for improved preventative strategies. Our laboratory has previously demonstrated in an experimental bone marrow transplantation (BMT) model that bendamustine combined with total body irradiation (BEN+TBI) is a safer alternative to cyclophosphamide with TBI (CY+TBI). The biological mechanisms of action of BEN have not been fully elucidated and likely involve multiple cell populations. Host dendritic cells (DCs) can prime naïve donor T-cells immediately following transplantation, making host DCs critical for the initiation phase of GvHD. We hypothesized that BEN+TBI conditioning favorably alters host DC composition to reduce GvHD. We demonstrate that host DCs treated with BEN+TBI induce less allogeneic T-cell proliferation than those conditioned with CY+TBI. We further show that BEN+TBI conditioning results in greater total numbers of all host DC subsets but with a more favorable composition compared to CY+TBI with significantly larger proportions of type 1 conventional DCs (cDC1), a highly regulatory DC subset capable of suppressing GvHD. Our studies using recipient Batf3 KO mice indicate that CD8α+ cDC1s are largely dispensable for the reduced GvHD following BEN+TBI conditioning. We found a higher frequency of host pre-cDC1s with BEN+TBI conditioning in both wild-type (WT) and Batf3 KO mice, which was inversely associated with GvHD. Additionally, we observed that BEN treatment results in greater expression of Flt3 receptor (CD135) on host DCs compared to CY, potentially contributing to the skewing of host DCs toward cDC1s. Further, BEN+TBI conditioning results in host cDCs with greater expression of PIR-B, an inhibitory receptor capable of preventing lethal GvHD. We conclude that BEN+TBI is a safer alternative to CY+TBI, resulting in a greater frequency of host pre-cDC1s and limiting GvHD.
• Moreno-Villanueva, M., Krieger, S., Zhang, Y. e., Feiveson, A., Berres, M., Splinter, S., Rithidech, K., Simpson, R., Crucian, B., & Wu, H. (2020). Gene and MicroRNA Expression Profile Changes in ISS Crewmembers’ Blood Samples.
• Mylabathula, P. L., Li, L. i., Bigley, A. B., Markofski, M. M., Crucian, B. E., Mehta, S. K., Pierson, D. L., Laughlin, M. S., Rezvani, K., & Simpson, R. J. (2020). Simulated microgravity disarms human NK-cells and inhibits anti-tumor cytotoxicity in vitro. Acta Astronautica, 174, 32--40.
• Niemiro, G. M., Coletta, A. M., Brewster, A. M., Bevers, T. B., Agha, N. H., Baker, F. L., Basen-Engquist, K., Katsanis, E., Gilchrist, S., & Simpson, R. J. (2020). T-cell Response To Exercise Training Among Women At Heightened Risk Of Breast Cancer.: 2458 Board# 4 May 29 9: 30 AM-11: 30 AM. Medicine & Science in Sports & Exercise, 52(7S), 665.
• Rawcliffe, A. J., Graham, S. M., Simpson, R. J., Moir, G. L., Martindale, R. J., Psycharakis, S. G., & Connaboy, C. (2020). The Effects of British Army Footwear on Ground Reaction Force and Temporal Parameters of British Army Foot Drill. The Journal of Strength & Conditioning Research, 34(3), 754--762.
• Simpson, R. J., & Katsanis, E. (2020). The immunological case for staying active during the COVID-19 pandemic. Brain, behavior, and immunity, 87, 6-7.
• Simpson, R. J., Campbell, J. P., Gleeson, M., Krüger, K., Nieman, D. C., Pyne, D. B., Turner, J. E., & Walsh, N. P. (2020). Can exercise affect immune function to increase susceptibility to infection?. Exercise immunology review, 26, 8-22.
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  Multiple studies in humans and animals have demonstrated the profound impact that exercise can have on the immune system. There is a general consensus that regular bouts of short-lasting (i.e. up to 45 minutes) moderate intensity exercise is beneficial for host immune defense, particularly in older adults and people with chronic diseases. In contrast, infection burden is reported to be high among high performance athletes and second only to injury for the number of training days lost during preparation for major sporting events. This has shaped the common view that arduous exercise (i.e. those activities practiced by high performance athletes/ military personnel that greatly exceed recommended physical activity guidelines) can suppress immunity and increase infection risk. However, the idea that exercise per se can suppress immunity and increase infection risk independently of the many other factors (e.g. anxiety, sleep disruption, travel, exposure, nutritional deficits, environmental extremes, etc.) experienced by these populations has recently been challenged. The purpose of this debate article was to solicit opposing arguments centered around this fundamental question in the exercise immunology field: can exercise affect immune function to increase susceptibility to infection. Issues that were contested between the debating groups include: (i) whether or not athletes are more susceptible to infection (mainly of the upper respiratory tract) than the general population; (ii) whether exercise per se is capable of altering immunity to increase infection risk independently of the multiple factors that activate shared immune pathways and are unique to the study populations involved; (iii) the usefulness of certain biomarkers and the interpretation of in vitro and in vivo data to monitor immune health in those who perform arduous exercise; and (iv) the quality of scientific evidence that has been used to substantiate claims for and against the potential negative effects of arduous exercise on immunity and infection risk. A key point of agreement between the groups is that infection susceptibility has a multifactorial underpinning. An issue that remains to be resolved is whether exercise per se is a causative factor of increased infection risk in athletes. This article should provide impetus for more empirical research to unravel the complex questions that surround this contentious issue in the field of exercise immunology.
• Smith, K. A., Agha, N. H., Baker, F. L., Bigley, A. B., Kunz, H. E., Niemiro, G. M., Colombo, J. N., Bond, R. A., Bollard, C. M., Katsanis, E., & others, . (2020). Systemic $beta$1-Adrenergic Receptor Blockade Augments NK-Cell Mobilization In Response To Acute Exercise In Humans: 120 May 27 11: 00 AM-11: 15 AM. Medicine & Science in Sports & Exercise, 52(7S), 16.
• Stokes, J., Hoffman, E. A., Molina, M. S., Kummet, N., Simpson, R. J., Zeng, Y., & Katsanis, E. (2020). Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia. Oncoimmunology, 9(1), 1758011.
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  Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.
• Agha, N. H., Baker, F. L., Kunz, H. E., Spielmann, G., Mylabathula, P. L., Rooney, B. V., Mehta, S. K., Pierson, D. L., Laughlin, M. S., Markofski, M. M., Crucian, B. E., & Simpson, R. J. (2019). Salivary antimicrobial proteins and stress biomarkers are elevated during a 6-month mission to the International Space Station. Journal of applied physiology (Bethesda, Md. : 1985).
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  As the international space community plans for manned missions to Mars, spaceflight associated immune dysregulation has been identified as a potential risk to the health and safety of the flight crew. There is a need to determine if salivary antimicrobial proteins - which act as a first line of innate immune defense against multiple pathogens - are altered in response to long-duration (>6-months) missions. We collected 7 consecutive days of saliva samples from 8 international space station (ISS) crewmembers and 7 ground-based controls at 9 separate mission time points; ~180 and ~60 days before launch (L-180/L-60), on orbit at flight day ~10 and ~90 (FD10/FD90) and ~1-day before return (R-1), and at R+0, R+18, R+33 and R+66 days after returning to Earth. We found that salivary sIgA, lysozyme, LL-37, and the cortisol to DHEA ratio were elevated in the ISS crew before (L-180) and during (FD10/FD90) the mission. 'Rookie' crewmembers embarking on their first spaceflight mission had lower levels of salivary sIgA, but increased levels of α-amylase, lysozyme and LL-37 during and after the mission compared to the 'veteran' crew who had previously flown. Latent herpesvirus reactivation was distinct to the ~6-month mission crewmembers who performed extravehicular activity ('spacewalks'). Crewmembers who shed at least one latent virus had higher cortisol levels compared to those who did not shed. We conclude that long-duration spaceflight alters the concentration and/or secretion of several antimicrobial proteins in saliva, some of which are related to crewmember flight experience, biomarkers of stress and latent viral reactivation.
• Bower, J. L., Laughlin, M. S., Connaboy, C., Simpson, R. J., & Alfano, C. A. (2019). Factor structure and validation of the mental health checklist (MHCL) for use in isolated, confined and extreme environments. Acta Astronautica, 161, 405--414.
• Connaboy, C., Johnson, C. D., LaGoy, A. D., Pepping, G. J., Simpson, R. J., Deng, Z., Ma, L., Bower, J. L., Eagle, S. R., Flanagan, S. D., & Alfano, C. A. (2019). Intersession Reliability and Within-Session Stability of a Novel Perception-Action Coupling Task. Aerospace medicine and human performance, 90(2), 77-83.
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  The perception-action coupling task (PACT) was designed as a more ecologically valid measure of alertness/reaction times compared to currently used measures by aerospace researchers. The purpose of this study was to assess the reliability, within-subject variability, and systematic bias associated with the PACT. There were 16 subjects (men/women = 9 / 7; age = 27.8 ± 3.6 yr) who completed 4 identical testing sessions. The PACT requires subjects to make judgements on whether a virtual ball could fit into an aperture. For each session, subjects completed nine cycles of the PACT, with each cycle lasting 5 min. Judgement accuracy and reaction time parameters were calculated for each cycle. Systematic bias was assessed with repeated-measures ANOVA, reliability with intraclass correlation coefficients (ICC), and within-subject variability with coefficients of variation (CV). Initiation time (Mean = 0.1065 s) showed the largest systematic bias, requiring the elimination of three cycles to reduce bias, with all other variables requiring, at the most, one. All variables showed acceptable reliability (ICC > 0.70) and within-subject variability (CV < 20%) with only one cycle after elimination of the first three cycles. With a three-cycle familiarization period, the PACT was found to be reliable and stable.
• Duggal, N. A., Niemiro, G., Harridge, S. D., Simpson, R. J., & Lord, J. M. (2019). Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?. Nature reviews. Immunology, 19(9), 563-572.
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  Remodelling of the immune system with age - immunosenescence - is a substantial contributor to poor health in older adults, with increasing risk of infections, cancer and chronic inflammatory disease contributing to age-related multi-morbidity. What is seldom considered when examining the immune response of an aged individual is that the immune system is profoundly influenced by physical activity. Habitual physical activity levels decline with age, with significant consequences for muscle mass and function. Skeletal muscle is a major immune regulatory organ and generates a range of proteins, termed myokines, which have anti-inflammatory and immunoprotective effects. Several studies indicate that maintaining physical activity has immune benefits in older adults, for example, it reduces the systemic inflammation associated with chronic age-related diseases. Here, we discuss how physical activity can prevent or ameliorate age-related multi-morbidity by boosting immune function, and we consider whether physical activity could improve immunotherapy outcomes in age-related conditions such as cancer.
• Johnson, C. D., LaGoy, A. D., Pepping, G. J., Eagle, S. R., Beethe, A. Z., Bower, J. L., Alfano, C. A., Simpson, R. J., & Connaboy, C. (2019). Action Boundary Proximity Effects on Perceptual-Motor Judgments. Aerospace medicine and human performance, 90(12), 1000-1008.
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  Designed as a more ecological measure of reaction times, the Perception-Action Coupling Task (PACT) has shown good reliability and within-subject stability. However, a lengthy testing period was required. Perceptual-motor judgments are known to be affected by proximity of the stimulus to the action boundary. The current study sought to determine the effects of action boundary proximity on PACT performance, and whether redundant levels of stimuli, eliciting similar responses, can be eliminated to shorten the PACT. There were 9 men and 7 women who completed 4 testing sessions, consisting of 3 familiarization cycles and 6 testing cycles of the PACT. For the PACT, subjects made judgments on whether a series of balls presented on a tablet afford "posting" (can fit) through a series of apertures. There were 8 ratios of ball to aperture size (B-AR) presented, ranging from 0.2 to 1.8, with each ratio appearing 12 times (12 trials) per cycle. Reaction times and judgment accuracy were calculated, and averaged across all B-ARs. Ratios and individual trials within each B-AR were systematically eliminated. Variables were re-averaged, and intraclass correlation coefficients (ICC) and coefficients of variation (CV) were calculated in an iterative manner. With elimination of the 0.2 and 1.8 B-ARs, the PACT showed good reliability (ICC = 0.81-0.99) and consistent within-subject stability (CV = 2.2-14.7%). Reliability (ICC = 0.81-0.97) and stability (CV = 2.6-15.6%) were unaffected with elimination of up to 8 trials from each B-AR. The shortened PACT resulted in an almost 50% reduction in total familiarization/testing time required, significantly increasing usability.
• Katsanis, E., Stokes, J., Hoffman, E., Maher, K. R., Kodali, M. K., Anwer, F., McBride, A., Roe, D., Zeng, Y. i., & Simpson, R. (2019). A Phase I Study of Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide and/or Bendamustine. Biology of Blood and Marrow Transplantation, 25(3), S224.
• LaGoy, A., Sinnott, A., Krajewski, K., Simpson, R. J., Bower, J. L., Alfano, C. A., & Connaboy, C. (2019). Action Boundary Perception Across 30 Days in an Isolated and Confined Environment: 2051 Board# 207 May 30 2: 00 PM-3: 30 PM. Medicine & Science in Sports & Exercise, 51(6S), 556.
• Makedonas, G., Mehta, S., Choukèr, A., Simpson, R. J., Marshall, G., Orange, J. S., Aunon-Chancellor, S., Smith, S. M., Zwart, S. R., Stowe, R. P., Heer, M., Ponomarev, S., Whitmire, A., Frippiat, J. P., Douglas, G. L., Krieger, S. S., Lorenzi, H., Buchheim, J. I., Ginsburg, G. S., , Ott, C. M., et al. (2019). Specific Immunologic Countermeasure Protocol for Deep-Space Exploration Missions. Frontiers in immunology, 10, 2407.
• Markofski, M. M., Baker, F. L., Simpson, R. J., & Agha, N. H. (2019). Exercise-induced Changes In Circulating Follistatin And GDF-15 Are Intensity-And Duration-dependent: 1879: Board# 35 May 30 2: 00 PM-3: 30 PM. Medicine & Science in Sports & Exercise, 51(6), 499.
• Ngo-Huang, A. n., Parker, N. H., Bruera, E., Lee, R. E., Simpson, R., O’Connor, D. P., Petzel, M. Q., Fontillas, R. C., Schadler, K., Xiao, L., & others, . (2019). Home-based exercise prehabilitation during preoperative treatment for pancreatic cancer is associated with improvement in physical function and quality of life. Integrative cancer therapies, 18, 1534735419894061.
• Parker, N. H., Lee, R. E., O’Connor, D. P., Ngo-Huang, A. n., Petzel, M. Q., Schadler, K., Wang, X., Xiao, L., Fogelman, D., Simpson, R., & others, . (2019). Supports and barriers to home-based physical activity during preoperative treatment of pancreatic cancer: a mixed-methods study. Journal of Physical Activity and Health, 16(12), 1113--1122.
• Parker, N. H., Ngo-Huang, A. n., Lee, R. E., O’Connor, D. P., Basen-Engquist, K. M., Petzel, M. Q., Wang, X., Xiao, L., Fogelman, D. R., Schadler, K. L., & others, . (2019). Physical activity and exercise during preoperative pancreatic cancer treatment. Supportive Care in Cancer, 27(6), 2275--2284.
• Simpson, R. J. (2019). 'Working-out' the link between inflammation and brain health. Brain, behavior, and immunity, 82, 6-7.
• Agha, N. H., Baker, F. L., Kunz, H. E., Graff, R., Azadan, R., Dolan, C., Laughlin, M. S., Hosing, C., Markofski, M. M., Bond, R. A., Bollard, C. M., & Simpson, R. J. (2018). Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the β2-adrenergic receptor. Brain, behavior, and immunity, 68, 66-75.
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  Acute dynamic exercise mobilizes CD34+ hematopoietic stem cells (HSCs) to the bloodstream, potentially serving as an economical adjuvant to boost the collection of HSCs from stem cell transplant donors. The mechanisms responsible for HSC mobilization with exercise are unknown but are likely due to hemodynamic perturbations, endogenous granulocyte-colony stimulating factor (G-CSF), and/or β2-adrenergic receptor (β2-AR) signaling. We characterized the temporal response of HSC mobilization and plasma G-CSF following exercise, and determined the impact of in vivo β-AR blockade on the exercise-induced mobilization of HSCs. Healthy runners (n = 15) completed, in balanced order, two single bouts of steady state treadmill running exercise at moderate (lasting 90-min) or vigorous (lasting 30-min) intensity. A separate cohort of healthy cyclists (n = 12) completed three 30-min cycling ergometer trials at vigorous intensity after ingesting: (i) 10 mg bisoprolol (β1-AR antagonist); (ii) 80 mg nadolol (β1 + β2-AR antagonist); or (iii) placebo, in balanced order with a double-blind design. Blood samples collected before, during (runners only), immediately after, and at several points during exercise recovery were used to determine circulating G-CSF levels (runners only) and enumerate CD34+ HSCs by flow cytometry (runners and cyclists). Steady state vigorous but not moderate intensity exercise mobilized HSCs, increasing the total blood CD34+ count by ∼4.15 ± 1.62 Δcells/µl (+202 ± 92%) compared to resting conditions. Plasma G-CSF increased in response to moderate but not vigorous exercise. Relative to placebo, nadolol and bisoprolol lowered exercising heart rate and blood pressure to comparable levels. The number of CD34+ HSCs increased with exercise after the placebo and bisoprolol trials, but not the nadolol trial, suggesting β2-AR signaling mediated the mobilization of CD34+ cells [Placebo: 2.10 ± 1.16 (207 ± 69.2%), Bisoprolol 1.66 ± 0.79 (+163 ± 29%), Nadolol: 0.68 ± 0.54 (+143 ± 36%) Δcells/µL]. We conclude that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of β2-AR signaling and hemodynamic shear stress.
• Bigley, A. B., Agha, N. H., Baker, F. L., Spielmann, G., Kunz, H. E., Mylabathula, P. L., Rooney, B., Laughlin, M. S., Pierson, D. L., Mehta, S. K., Crucian, B. E., & Simpson, R. J. (2018). NK-cell function is impaired during long-duration spaceflight. Journal of applied physiology (Bethesda, Md. : 1985).
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  Maintaining astronaut health during space travel is paramount for further human exploration of the solar system beyond Earth's orbit. Of concern are potential dysregulations in immunity, which could impair protection against cancer and latent viral reactivation. We compared changes in NK-cell phenotype and function in 8 crewmembers who completed a ~6-month mission to the International Space Station (ISS) with healthy controls who remained on Earth. Assessments were made before [(-180 and -60 days before launch (L)], during [flight day (FD) +90 and 1 day prior to return (R) -1], and after the mission at days R+0, R+18, R+33, and R+66. These samples, plus an additional in flight sample (FD+180), were collected from a crewmember who spent 340 days (~1-year) on the ISS. NK-cell cytotoxic activity (NKCA) against K562 leukemia targets in vitro was reduced by ~50% at FD+90 in ISS crew but not controls. This decrease was more pronounced in 'rookie' compared to 'veteran' crewmembers. The ~1-year mission crewmember did not show declines in NKCA against K562 until late in the mission (R-1 and R+0). NK-cell numbers, expression of activating and inhibitory receptors, target cell binding, and expression and degranulation of perforin and granzyme b were unaltered with spaceflight. Similarly, exposing the NK-92 cell line to sera collected at different mission time-points did not affect NKCA. This is the first study to report impaired NK-cell function during long duration space travel. Countermeasures may be needed to mitigate immune system impairment in exploration class mission crew during long duration spaceflight missions.
• Bigley, A. B., Baker, F. L., & Simpson, R. J. (2018). Cytomegalovirus: an unlikely ally in the fight against blood cancers?. Clinical and experimental immunology, 193(3), 265-274.
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  Cytomegalovirus (CMV) infection is a potentially fatal complication in patients receiving haematopoietic stem cell transplantation (HSCT), but recent evidence indicates that CMV has strong anti-leukaemia effects due in part to shifts in the composition of natural killer (NK) cell subsets. NK cells are the primary mediators of the anti-leukaemia effect of allogeneic HSCT, and infusion of allogeneic NK cells has shown promise as a means of inducing remission and preventing relapse of several different haematological malignancies. The effectiveness of these treatments is limited, however, when tumours express human leucocyte antigen (HLA)-E, a ligand for the inhibitory receptor NKG2A, which is expressed by the vast majority of post-transplant reconstituted and ex-vivo expanded NK cells. It is possible to enhance NK cell cytotoxicity against HLA-E malignancies by increasing the proportion of NK cells expressing NKG2C (the activating receptor for HLA-E) and lacking the corresponding inhibitory receptor NKG2A. The proportion of NKG2C /NKG2A NK cells is typically low in healthy adults, but it can be increased by CMV infection or ex-vivo expansion of NK cells using HLA-E-transfected feeder cells and interleukin (IL)-15. In this review, we will discuss the role of CMV-driven NKG2C /NKG2A NK cell expansion on anti-tumour cytotoxicity and disease progression in the context of haematological malignancies, and explore the possibility of harnessing NKG2C /NKG2A NK cells for cancer immunotherapy.
• Crucian, B. E., Choukèr, A., Simpson, R. J., Mehta, S., Marshall, G., Smith, S. M., Zwart, S. R., Heer, M., Ponomarev, S., Whitmire, A., Frippiat, J. P., Douglas, G. L., Lorenzi, H., Buchheim, J. I., Makedonas, G., Ginsburg, G. S., Ott, C. M., Pierson, D. L., Krieger, S. S., , Baecker, N., et al. (2018). Immune System Dysregulation During Spaceflight: Potential Countermeasures for Deep Space Exploration Missions. Frontiers in immunology, 9, 1437.
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  Recent studies have established that dysregulation of the human immune system and the reactivation of latent herpesviruses persists for the duration of a 6-month orbital spaceflight. It appears certain aspects of adaptive immunity are dysregulated during flight, yet some aspects of innate immunity are heightened. Interaction between adaptive and innate immunity also seems to be altered. Some crews experience persistent hypersensitivity reactions during flight. This phenomenon may, in synergy with extended duration and galactic radiation exposure, increase specific crew clinical risks during deep space exploration missions. The clinical challenge is based upon both the frequency of these phenomena in multiple crewmembers during low earth orbit missions and the inability to predict which specific individual crewmembers will experience these changes. Thus, a general countermeasure approach that offers the broadest possible coverage is needed. The vehicles, architecture, and mission profiles to enable such voyages are now under development. These include deployment and use of a cis-Lunar station (mid 2020s) with possible Moon surface operations, to be followed by multiple Mars flyby missions, and eventual human Mars surface exploration. Current ISS studies will continue to characterize physiological dysregulation associated with prolonged orbital spaceflight. However, sufficient information exists to begin consideration of both the need for, and nature of, specific immune countermeasures to ensure astronaut health. This article will review relevant in-place operational countermeasures onboard ISS and discuss a myriad of potential immune countermeasures for exploration missions. Discussion points include nutritional supplementation and functional foods, exercise and immunity, pharmacological options, the relationship between bone and immune countermeasures, and vaccination to mitigate herpes (and possibly other) virus risks. As the immune system has sentinel connectivity within every other physiological system, translational effects must be considered for all potential immune countermeasures. Finally, we shall discuss immune countermeasures in the context of their individualized implementation or precision medicine, based on crewmember specific immunological biases.
• Graff, R. M., Kunz, H. E., Agha, N. H., Baker, F. L., Laughlin, M., Bigley, A. B., Markofski, M. M., LaVoy, E. C., Katsanis, E., Bond, R. A., Bollard, C. M., & Simpson, R. J. (2018). β-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans. Brain, behavior, and immunity, 74, 143-153.
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  Acute exercise preferentially mobilizes cytotoxic T-cells, NK-cells and non-classical monocytes to the bloodstream under the influence of hemodynamic forces and/or β-adrenergic receptor (β-AR) signaling. However, the relative contribution of these mechanisms to the redeployment of the most exercise-responsive cell types is largely unknown. We determined the lymphocyte and monocyte subtypes mobilized to blood during exercise via β-AR signaling whilst controlling for β-AR mediated reductions in hemodynamic forces. In a randomized, double blind, complete cross-over design, 14 healthy cyclists exercised for 30-minutes at +10% of blood lactate threshold after ingesting: (1) a placebo, (2) a β-preferential antagonist (10 mg bisoprolol), or (2) a non-preferential β + β-antagonist (80 mg nadolol) across three trials separated by >7-days. Bisoprolol was administered to reduce hemodynamic forces (heart rate and blood pressure) during exercise to levels comparable with nadolol but without blocking β-ARs. The mobilization of total NK-cells, terminally differentiated (CD57+) NK-cells, central memory, effector memory and CD45RA+ effector memory CD8+ T-cells; non-classical monocytes; and γδ T-cells were significantly blunted or abrogated under nadolol compared to both bisoprolol and placebo, indicating that the exercise-induced mobilization of these cell types to the blood is largely influenced by β-AR signaling. Nadolol failed to inhibit the mobilization of classical monocytes, CD4+ T-cells (and their subsets) or naïve CD8+ T-cells, indicating that these cell types are mobilized with exercise independently of the β-AR. We conclude that the preferential mobilization of NK-cells, non-classical monocytes and differentiated subsets of CD8+ T-cells with exercise is largely dependent on catecholamine signaling through the β-AR. These findings provide mechanistic insights by which distinct lymphocyte and monocyte subtypes are preferentially mobilized to protect the host from anticipated injury or infection in response to an acute stress response.
• Kunz, H. E., Spielmann, G., Agha, N. H., O'Connor, D. P., Bollard, C. M., & Simpson, R. J. (2018). A single exercise bout augments adenovirus-specific T-cell mobilization and function. Physiology & behavior, 194, 56-65.
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  Adoptive transfer of virus-specific T-cells (VSTs) effectively treats viral infections following allogeneic hematopoietic stem cell transplantation (alloHSCT), but logistical difficulties have limited widespread availability of VSTs as a post-transplant therapeutic. A single exercise bout mobilizes VSTs specific for latent herpesviruses (i.e. CMV and EBV) to peripheral blood and augments their ex vivo expansion. We investigated whether exercise exerts similar effects on T-cells specific for a NON-latent virus such as adenovirus, which is a major contributor to infection-related morbidity and mortality after alloHSCT. Thirty minutes of cycling exercise increased circulating adenovirus-specific T-cells 2.0-fold and augmented their ex vivo expansion by ~33% compared to rest without altering antigen and MHC-specific autologous target cell killing capabilities. We conclude that exercise is a simple and economical adjuvant to boost the isolation and manufacture of therapeutic VSTs specific to latent and non-latent viruses from healthy donors.
• Parker, N. H., Ngo-Huang, A., Lee, R. E., O'Connor, D. P., Basen-Engquist, K. M., Petzel, M. Q., Wang, X., Xiao, L., Fogelman, D. R., Schadler, K. L., Simpson, R. J., Fleming, J. B., Lee, J. E., Varadhachary, G. R., Sahai, S. K., & Katz, M. H. (2018). Physical activity and exercise during preoperative pancreatic cancer treatment. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer.
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  Guidelines recommend exercise to cancer survivors, but limited data exists regarding exercise among patients undergoing preoperative cancer treatment. We examined differences in weekly self-reported exercise and accelerometer-measured physical activity among participants in a home-based exercise program administered during preoperative treatment for pancreatic cancer.
• Rooney, B. V., Bigley, A. B., LaVoy, E. C., Laughlin, M., Pedlar, C., & Simpson, R. J. (2018). Lymphocytes and monocytes egress peripheral blood within minutes after cessation of steady state exercise: A detailed temporal analysis of leukocyte extravasation. Physiology & behavior, 194, 260-267.
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  Acute exercise evokes an almost instantaneous lymphocytosis, followed by sustained lymphopenia that occurs within just 30-60 min after exercise cessation. The aim of this study was to characterize the immediate (order of minutes) post-exercise kinetics of lymphocyte and monocyte egress, and to determine whether this egress is associated with heart rate recovery following a single bout of steady state dynamic exercise. Eleven healthy subjects cycled for 30-min at ~70% of their estimated peak power. Blood samples were collected from an intravenous catheter before exercise, during exercise (E) at +15 and +30 min, and during passive recovery (R) at exactly +1, +2, +3, +4, +5 and +10 min after exercise cessation. Complete blood counts and flow cytometry were used to enumerate total monocytes, lymphocytes: CD3+ T-cells, CD4+ T-cells, CD8+ T-cells, NK-cells and γδ T-cells in whole blood. Both lymphocytes and monocytes displayed rapid egress kinetics, by R+3 the total numbers of all cell types examined were significantly lower than E+30. NK-cells egressed more rapidly than other lymphocyte subtypes, followed by CD8+, γδ, and then CD4+ T-cells. Further, the egress of NK-cells, CD4+, and CD8+ T-cells positively correlated with heart rate recovery after exercise cessation. In conclusion, lymphocyte and monocyte egress is rapid and occurs within minutes of exercise recovery, underscoring both the importance of collection time for post exercise blood samples, and the use of intravenous catheters to capture peak cell mobilization. The rate of egress may be dependent on how quickly hemodynamic equilibrium is restored on cessation of exercise and is, therefore, likely to be influenced by individual fitness levels.
• Ross, M., Ingram, L., Taylor, G., Malone, E., Simpson, R. J., West, D., & Florida-James, G. (2018). Older men display elevated levels of senescence-associated exercise-responsive CD28 angiogenic T cells compared with younger men. Physiological reports, 6(12), e13697.
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  Aging is associated with elevated cardiovascular disease risk. As a result of aging, endothelial dysfunction develops, partly due to a reduction in vascular regenerative ability. CD31 T cells (angiogenic T cells; T ) possess highly angiogenic capabilities; however, these cells are significantly reduced in older populations. In addition, older populations possess significantly higher senescent and highly differentiated T-cell levels in circulation, and these are reported to be highly exercise responsive. We investigated whether older adults display greater levels of circulating senescent (CD28 ) T cells and whether these cells were more exercise responsive than CD28 T cells. Young (18-25 years; n = 9) and older (60-75 years; n = 10) healthy men undertook a 30-min cycling bout at 70% V˙O peak, with circulating T cells (CD3 CD31 CD28 ; including CD4 and CD8 subsets) measured preexercise, postexercise, and 1 h post exercise by flow cytometry. Older adults displayed reduced basal levels of T cells (mean ± SEM: 410 ± 81 vs. 784 ± 118 cells·μL, P = 0.017), despite a greater proportion of these cells being CD28 (26.26 ± 5.08 vs. 13.36 ± 2.62%, P = 0.044). Exercise significantly increased the circulating number of T cells in both young and older men. However, in older men alone, exercise preferentially mobilized CD28 CD8 T cells compared with CD28 T cells (time × phenotype interaction: P = 0.022; Δ74 ± 29 vs. Δ27 ± 15 cells·μL, P = 0.059), with no such difference observed between these phenotypes in the young population. In conclusion, this is the first study to demonstrate that despite observing lower circulating numbers of T cells, older adults display greater levels of senescent T cells in comparison with younger individuals, and these cells are more exercise responsive than CD28 T cells. Lower number of circulating T and greater levels of senescent-associated CD28 T may contribute to greater CVD risk with advancing age.
• Spielmann, G., Agha, N. H., Kunz, H. E., Simpson, R. J., Crucian, B. E., Mehta, S. K., Laughlin, M., & Campbell, J. (2018). B-cell homeostasis is maintained during long duration spaceflight. Journal of applied physiology (Bethesda, Md. : 1985).
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  Long duration spaceflights reportedly induce immune dysregulation, which is considered a risk to astronaut safety and mission success. Recent studies have examined the impact of spaceflight on markers of adaptive and innate immunity, but no study to date has comprehensively evaluated humoral immunity and serological markers of B-cell function. The aim of this study was to characterize changes in B-cell numbers and phenotypes, along with plasma immunoglobulins and polyclonal free light chains (FLC) - near 'real-time' biomarkers of immunoglobulin synthesis - in response to a ~6-month mission to the International Space Station (ISS). Blood samples were collected before flight, during ("Early flight", "Mid-flight" and "Late flight"), immediately upon return and during a recovery period (R+18, R+30/R+33 and R+60/R+66) from 23 ISS crewmembers. B-cell counts and phenotypes were measured throughout the duration of the mission, along with total plasma immunoglobulin (Ig) and FLC levels. There was no effect of spaceflight on the number and proportion of the different B-cell subsets. There was no difference in kappa FLC between pre-flight samples and either in-flight or recovery samples (p>0.05), and only a marginal reduction was observed in lambda FLC levels upon return to Earth (p0.05). Of note, plasma IgA concentrations were elevated in-flight when compared to baseline and recovery values (p
• Kunz, H., Quiriarte, H., Simpson, R. J., Ploutz-Snyder, R., McMonigal, K., Sams, C., & Crucian, B. (2017). Alterations in hematologic indices during long-duration spaceflight. BMC hematology, 17, 12.
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  Although a state of anemia is perceived to be associated with spaceflight, to date a peripheral blood hematologic assessment of red blood cell (RBC) indices has not been performed during long-duration space missions.
• LaVoy, E. C., Hussain, M., Reed, J., Kunz, H., Pistillo, M., Bigley, A. B., & Simpson, R. J. (2017). T-cell redeployment and intracellular cytokine expression following exercise: effects of exercise intensity and cytomegalovirus infection. Physiological reports, 5(1).
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  The magnitude of lymphocytosis following exercise is directly related to exercise intensity. Infection with cytomegalovirus (CMV) also augments lymphocytosis after exercise. It is not known if the enhanced T-cell response to exercise due to CMV depends on exercise intensity. Furthermore, exercise-induced changes in T-cell expression of type I and type II cytokines are thought to be intensity dependent, but direct comparisons are lacking. The aim of this experiment was to determine if CMV affects the exercise-induced redistribution of T-cell subsets at varying intensities, and determine the effect of exercise intensity on CD8+ T-cell cytokine expression. Seventeen cyclists (nine CMV seropositive; CMV+) completed three 30 min cycling trials at -5, +5, and +15% of blood lactate threshold (LT). T-cell subsets in blood and intracellular expression of type I (IL-2, interferon(IFN)-γ) and type II (IL-4, IL-10) cytokines by CD8+ T cells pre, post, and 1-h post-exercise were assessed by flow cytometry. Independently of CMV, T-cell subset redistribution was greater after +15%LT compared to -5%LT (P 
• Peake, J. M., Neubauer, O., Walsh, N. P., & Simpson, R. J. (2017). Recovery of the immune system after exercise. Journal of applied physiology (Bethesda, Md. : 1985), 122(5), 1077-1087.
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  The notion that prolonged, intense exercise causes an "open window" of immunodepression during recovery after exercise is well accepted. Repeated exercise bouts or intensified training without sufficient recovery may increase the risk of illness. However, except for salivary IgA, clear and consistent markers of this immunodepression remain elusive. Exercise increases circulating neutrophil and monocyte counts and reduces circulating lymphocyte count during recovery. This lymphopenia results from preferential egress of lymphocyte subtypes with potent effector functions [e.g., natural killer (NK) cells, γδ T cells, and CD8+ T cells]. These lymphocytes most likely translocate to peripheral sites of potential antigen encounter (e.g., lungs and gut). This redeployment of effector lymphocytes is an integral part of the physiological stress response to exercise. Current knowledge about changes in immune function during recovery from exercise is derived from assessment at the cell population level of isolated cells ex vivo or in blood. This assessment can be biased by large changes in the distribution of immune cells between blood and peripheral tissues during and after exercise. Some evidence suggests that reduced immune cell function in vitro may coincide with changes in vivo and rates of illness after exercise, but more work is required to substantiate this notion. Among the various nutritional strategies and physical therapies that athletes use to recover from exercise, carbohydrate supplementation is the most effective for minimizing immune disturbances during exercise recovery. Sleep is an important aspect of recovery, but more research is needed to determine how sleep disruption influences the immune system of athletes.
• Rawcliffe, A. J., Graham, S. M., Simpson, R. J., Moir, G. L., Martindale, R. J., Psycharakis, S. G., & Connaboy, C. (2017). The Effects of British Army Footwear on Ground Reaction Force and Temporal Parameters of British Army Foot-Drill. Journal of strength and conditioning research.
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  High rates of occupational training-related lower-limb musculoskeletal [MSK] overuse injuries are reported for British Army recruits during basic training. Foot-drill is a repetitive impact loading occupational activity and involves striking the ground violently with an extended-knee [straight-leg] landing. Foot-drill produces vertical ground reaction forces [vGRF] equal to and/or greater than those reported for high-level plyometric exercises/activities. Shock absorbing footwear aid in the attenuation of the magnitude of vGRF, resulting in a reduced risk of lower-limb MSK overuse injury when running. The potential shock absorbing characteristics of standard issue British Army footwear on the magnitude of vGRF and temporal parameters of foot-drill are scant. Therefore, this study sought to determine the magnitude of, and examine changes in vGRF and temporal parameters of foot-drill across three types of British Army footwear. Sampled at 1000hz, the mean of eight-trials from fifteen recreationally active males were collected from four foot-drills; stand-at-ease [SaE], stand-at-attention [SaA], quick-march [QM] and halt. Analysis of a normal walk was included to act as a comparison with quick-march. Significant main effects [P
• Rawcliffe, A. J., Simpson, R. J., Graham, S. M., Psycharakis, S. G., Moir, G. L., & Connaboy, C. (2017). Reliability of the Kinetics of British Army Foot Drill in Untrained Personnel. Journal of strength and conditioning research, 31(2), 435-444.
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  Rawcliffe, AJ, Simpson, RJ, Graham, SM, Psycharakis, SG, Moir, GL, and Connaboy, C. Reliability of the kinetics of British Army foot drill in untrained personnel. J Strength Cond Res 31(2): 435-444, 2017-The purpose of this study was to quantify the reliability of kinetic variables of British Army foot drill performance within untrained civilians and report the magnitude of vertical ground reaction force (vGRF) and vertical rate of force development (RFD) of foot drills. Fifteen recreational active males performed 3 testing sessions across a 1-week period, with each session separated by 24 hours. Within each testing session participants (mean ± SD; age 22.4 ± 1.7 years; height 177 ± 5.6 cm; weight 83 ± 8.7 kg) completed 10 trials of stand-at-attention (SaA), stand-at-ease (SaE), Halt, quick-march (QM) and a normal walking gait, with vGRF and vertical RFD measured on a force plate. Between-session and within-session reliability was calculated as systematic bias, coefficient of variation calculated from the typical error (CVte%), and intraclass correlation coefficient (ICC). Significant (p ≤ 0.05) between-session differences were found for the vGRF SaA and SaE, and vertical RFD SaA and SaE conditions. Significant (p ≤ 0.05) within-session differences were found for the vGRF SaA and SaE conditions. A mean vGRF CVte% ≤10% was observed across all foot drills. However, the mean vertical RFD CVte% observed was ≥10% (excluding SaE) across all foot drills. The ICC analyses indicated that the vGRF Halt, QM, SaA, and Walk condition achieved moderate to large levels of test-retest reliability, with only SaE failing to achieve an ICC value ≥0.75. The vertical RFD QM, SaE, and Walk condition achieved moderate levels of test-retest reliability, with Halt and SaA failing to achieve an ICC value ≥0.75. It was determined that a single familiarization session and using the mean of 8 trials of vGRF are required to achieve acceptable levels of reliability.
• Simpson, R. J., Bigley, A. B., Agha, N., Hanley, P. J., & Bollard, C. M. (2017). Mobilizing Immune Cells With Exercise for Cancer Immunotherapy. Exercise and sport sciences reviews, 45(3), 163-172.
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  Hematopoietic stem cell (HSC) transplantation and adoptive transfer immunotherapy are effective in treating blood cancers and posttransplant infections, but low-circulating cell numbers in patients and donors are oftentimes a limiting factor. We postulate that a single exercise bout will increase the yield of patient- and donor-derived HSCs and cytotoxic lymphocytes to improve this form of treatment for cancer patients.
• Simpson, R. J., Graham, S. M., Connaboy, C., Clement, R., Pollonini, L., & Florida-James, G. D. (2017). Blood lactate thresholds and walking/running economy are determinants of backpack-running performance in trained soldiers. Applied ergonomics, 58, 566-572.
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  We developed a standardized laboratory treadmill protocol for assessing physiological responses to a simulated backpack load-carriage task in trained soldiers, and assessed the efficacy of blood lactate thresholds (LTs) and economy in predicting future backpack running success over an 8-mile course in field conditions. LTs and corresponding physiological responses were determined in 17 elite British soldiers who completed an incremental treadmill walk/run protocol to exhaustion carrying 20 kg backpack load. Treadmill velocity at the breakpoint (r = -0.85) and Δ 1 mmol l(-1) (r = -0.80) LTs, and relative V˙O2 at 4 mmol l(-1) (r = 0.76) and treadmill walk/run velocities of 6.4 (r = 0.76), 7.4 (r = 0.80), 11.4 (r = 0.66) and 12.4 (r = 0.65) km h(-1) were significantly associated with field test completion time. We report for the first time that LTs and backpack walk/run economy are major determinants of backpack load-carriage performance in trained soldiers.
• Bigley, A. B., Rezvani, K., Shah, N., Sekine, T., Balneger, N., Pistillo, M., Agha, N., Kunz, H., O'Connor, D. P., Bollard, C. M., & Simpson, R. J. (2016). Latent cytomegalovirus infection enhances anti-tumour cytotoxicity through accumulation of NKG2C+ NK cells in healthy humans. Clinical and experimental immunology, 185(2), 239-51.
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  Cytomegalovirus (CMV) infection markedly expands NKG2C+/NKG2A- NK cells, which are potent killers of infected cells expressing human leucocyte antigen (HLA)-E. As HLA-E is also over-expressed in several haematological malignancies and CMV has been linked to a reduced risk of leukaemic relapse, we determined the impact of latent CMV infection on NK cell cytotoxicity against four tumour target cell lines with varying levels of HLA-E expression. NK cell cytotoxicity against K562 (leukaemia origin) and U266 (multiple myeloma origin) target cells was strikingly greater in healthy CMV-seropositive donors than seronegative donors and was associated strongly with target cell HLA-E and NK cell NKG2C expression. NK cell cytotoxicity against HLA-E transfected lymphoma target cells (221.AEH) was ∼threefold higher with CMV, while NK cell cytotoxicity against non-transfected 721.221 cells was identical between the CMV groups. NK cell degranulation (CD107a(+) ) and interferon (IFN)-γ production to 221.AEH cells was localized almost exclusively to the NKG2C subset, and antibody blocking of NKG2C completely eliminated the effect of CMV on NK cell cytotoxicity against 221.AEH cells. Moreover, 221.AEH feeder cells and interleukin (IL)-15 were found to expand NKG2C(+) /NKG2A(-) NK cells preferentially from CMV-seronegative donors and increase NK cell cytotoxicity against HLA-E(+) tumour cell lines. We conclude that latent CMV infection enhances NK cell cytotoxicity through accumulation of NKG2C(+) NK cells, which may be beneficial in preventing the initiation and progression of haematological malignancies characterized by high HLA-E expression.
• Bigley, A. B., Spielmann, G., Agha, N., O'Connor, D. P., & Simpson, R. J. (2016). Dichotomous effects of latent CMV infection on the phenotype and functional properties of CD8+ T-cells and NK-cells. Cellular immunology, 300, 26-32.
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  CMV markedly alters the phenotype and function of NK-cells and T-cells and has been linked to immunosenescence. We show here that subjects with effective CMV control (evidenced by low CMV IgG titers) have functional responses to CMV that are driven by either NKG2C+ NK-cells or CMV-specific T-cells (15 of 24 subjects), but not both. These data indicate that people with effective CMV control are either NK-cell or T-cell responders, and corroborates the idea that NK-cells have rheostat-like properties that regulate anti-viral T-cell responses. Whether or not lifelong CMV control through either NK-cell or T-cell responses have implications for immunosenescence remains to be determined.
• Fiuza-Luces, C., Simpson, R. J., Ramírez, M., Lucia, A., & Berger, N. A. (2016). Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients. Bone marrow transplantation, 51(1), 13-26.
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  Allogeneic hematopoietic stem cell transplant, to reconstitute the hematopoietic and immune status of patients undergoing myeloablative therapy for hematologic disorders, has been of great benefit in minimizing or eradicating disease and extending survival. Patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) are subject to many comorbidities among which the most significant, affecting quality of life (QoL) and survival, are acute GvHD (aGvHD) and chronic GvHD (cGvHD), resulting from donor lymphocytes reacting to and damaging host tissues. Physical activity and exercise have clearly been shown, in both children and adults, to enhance fitness, improve symptomatology and QoL, reduce disease progression and extend survival for many diseases including malignancies. In some cases, vigorous exercise has been shown to be equal to or more effective than pharmacologic therapy. This review addresses how cGvHD affects patients' physical function and physical domain of QoL, and the potential benefits of exercise interventions along with recommendations for relevant research and evaluation targeted at incorporating this strategy as soon as possible after allo-HSCT and ideally, as soon as possible upon diagnosis of the condition leading to allo-HSCT.
• Leach, H. J., O'Connor, D. P., Simpson, R. J., Rifai, H. S., Mama, S. K., & Lee, R. E. (2016). An exploratory decision tree analysis to predict cardiovascular disease risk in African American women. Health psychology : official journal of the Division of Health Psychology, American Psychological Association, 35(4), 397-402.
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  African American (AA) women are at greater risk for cardiovascular disease (CVD) compared to White women, which can be attributed to disparities in risk factors. The built environment may contribute to improving CVD risk factors by increasing physical activity (PA). This study used recursive partitioning, a multivariate decision tree risk classification approach, to determine which built environment characteristics contributed to the classification of AA women as having 4 or more CVD risk factors at optimal levels.
• Simpson, R. J. (2016). Aging and inflammation: Directing traffic through physical activity. Brain, behavior, and immunity, 56, 10-1.
• Simpson, R. J., Bigley, A. B., Spielmann, G., LaVoy, E. C., Kunz, H., & Bollard, C. M. (2016). Human cytomegalovirus infection and the immune response to exercise. Exercise immunology review, 22, 8-27.
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  Human cytomegalovirus (HCMV) is a ubiquitous -herpes virus that has co-evolved with its host since the very beginning of human life. The vast majority of adults worldwide carry the virus in a latent state, which is known to have striking effects on the composition and function of both T-cells and NK-cells. While there is evidence to suggest that prior exposure to HCMV can have beneficial effects in the immune competent host, poor control of the virus may contribute to T-cell exhaustion and the early onset of immunosenescence. The interaction between HCMV and exercise has garnered a lot of recent research attention. This stemmed from observations that people with HCMV redeploy greater numbers of CD8+ T-cells in response to a single exercise bout, while NK-cell mobilization is, conversely, impaired. Moreover, athletes with latent HCMV infection may be better protected against symptoms of upper respiratory illness (URI), and it has been suggested that the host's ability to control HCMV (i.e. keeping CMV in a latent state) may connect apparent bidirectional effects of exercise volume on host immunity and infection risk. This work has set a new paradigm that immune responses to both acute and chronic exercise might be governed by the infection history of the host. In this review, we summarize current knowledge on the effects of HCMV infection on T-cells and NK-cells and synthesize the literature on HCMV and the immune response to both single exercise bouts and prolonged periods of exercise training. We also discuss potential clinical and practical applications of this work including the use of HCMV reactivation as a biomarker of immune depression in athletes, its relevance in immunosenescence and the associated immune risk profile, and the potential for exercise to augment vaccine responses and the man ufacture of immune cells for adoptive transfer immunotherapy. Although research in this area is still in its infancy, we conclude that host infection history and the ability to regulate dormant pathogens is likely to play a key role in our understanding of how the immune system responds to both acute and chronic exercise across the entire exercise volume continuum.
• Spielmann, G., Bollard, C. M., Kunz, H., Hanley, P. J., & Simpson, R. J. (2016). A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy. Scientific reports, 6, 25852.
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  Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exercise bout on the ex vivo manufacture of multi-VSTs. PBMCs isolated from healthy CMV/EBV seropositive participants before (PRE) and immediately after (POST) 30-minutes of cycling exercise were stimulated with CMV (pp65 and IE1) and EBV (LMP2A and BMLF1) peptides and expanded over 8 days. The number (fold difference from PRE) of T-cells specific for CMV pp65 (2.6), EBV LMP2A (2.5), and EBV BMLF1 (4.4) was greater among the VSTs expanded POST. VSTs expanded PRE and POST had similar phenotype characteristics and were equally capable of MHC-restricted killing of autologous target cells. We conclude that a single exercise bout enhances the manufacture of multi-VSTs from healthy donors without altering their phenotype or function and may serve as a simple and economical adjuvant to boost the production of multi-VSTs for allogeneic adoptive transfer immunotherapy.
• Turner, J. E., Spielmann, G., Wadley, A. J., Aldred, S., Simpson, R. J., & Campbell, J. P. (2016). Exercise-induced B cell mobilisation: Preliminary evidence for an influx of immature cells into the bloodstream. Physiology & behavior, 164(Pt A), 376-82.
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  The number of peripheral blood B lymphocytes doubles during acute exercise, but the phenotypic composition of this response remains unknown. In two independent exercise studies, using complimentary phenotyping strategies, we investigated the mobilisation patterns of distinct B cell subsets. In study one, nine healthy males (mean±SD age: 22.1±3.4years) completed a continuous cycling bout at 80% V̇O2MAX for 20min. In study two, seven healthy experienced cyclists (mean±SD age: 29.9±4.7years) completed a 30min cycling trial at a workload corresponding to +5% of the individual blood lactate threshold. In study one, CD3-CD19+ B cell subsets were classified into immature (CD27-CD10+), naïve (CD27-CD10-), memory (CD27+CD38-), plasma cells/plasmablasts (CD27+CD38+) and finally, recently purported 'B1' cells (CD27+ CD43+ CD69-). In study two, CD20+ B cells were classified into immature (CD27-IgD-), naïve (CD27-IgD+), and IgM+/IgG+/IgA+ memory cells (CD27+IgD-). Total B cells exhibited a mean increase of 88% (study one) and 60% (study two) during exercise. In both studies, immature cells displayed the greatest increase, followed by memory cells, then naïve cells (study one: immature 130%>mature 105%>naïve 84%; study two: immature 110%>mature 56%>naïve 38%). Our findings show that, unlike T cells and NK cells, B cell mobilisation is not driven by effector status, and, for the first time, that B cell mobilisation during exercise is comprised of immature CD27- IgD-/CD10+ cells.
• Bigley, A. B., & Simpson, R. J. (2015). NK cells and exercise: implications for cancer immunotherapy and survivorship. Discovery medicine, 19(107), 433-45.
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  Natural Killer (NK) cells are cytotoxic effectors of the innate immune system that are able to recognize and eradicate tumor cells without prior antigenic exposure. Tumor infiltration by NK-cells is associated with prolonged survival in cancer patients and high NK-cell cytotoxicity has been linked to decreased cancer risk. Allogeneic adoptive transfer of NK-cells from healthy donors to cancer patients has shown promise as a means of controlling or reversing the spread of multiple human malignancies including multiple myeloma and acute myeloid leukemia. However, multiple issues remain that undermine the efficacy of long-term cancer treatment using adoptive transfer of NK-cells including loss of activating receptors and cytotoxic potential in transferred NK-cells. Moreover, chronic exercise has been linked to improved NK-cell cytotoxicity, prognosis, and survival in cancer patients, and cytomegalovirus (CMV) reactivation is associated with enhanced NK-cell function after hematopoietic stem cell transplantation and decreased relapse risk in AML patients. In this work, we explore the potential of exercise- and CMV-driven alterations in NK-cell phenotype and function to increase the efficacy of NK-cells for cancer immunotherapy and prolong survival in cancer patients. We conclude that acute exercise and CMV are both capable of enhancing NK-cell cytotoxicity through distinct mechanisms; however, these effects are not additive as CMV infection is associated with an impaired acute exercise response. Thus, we suggest that either acute exercise or in vitro expansion of NKG2C+/NKG2A- NK-cells (as seen in those with CMV) could serve as a simple strategy for enhancing the anti-tumor cytotoxicity of NK-cells for immunotherapy, and that exercise training could be used to improve survivorship in cancer patients being treated with either HSCT or NK-cell infusions.
• Bigley, A. B., Spielmann, G., Agha, N., & Simpson, R. J. (2015). The Effects of Age and Latent Cytomegalovirus Infection on NK-Cell Phenotype and Exercise Responsiveness in Man. Oxidative medicine and cellular longevity, 2015, 979645.
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  The redeployment of NK-cells in response to an acute bout of exercise is thought to be an integral component of the "fight-or-flight" response, preparing the body for potential injury or infection. We showed previously that CMV seropositivity impairs the redeployment of NK-cells with exercise in the young. In the current study, we examined the effect of aging on the redeployment of NK-cells with exercise in the context of CMV. We show here that CMV blunts the exercise-induced redeployment of NK-cells in both younger (23-39 yrs) and older (50-64 yrs) subjects with older CMV(neg) subjects showing the largest postexercise mobilization and 1 h postexercise egress of NK-cells. The blunted exercise response in CMV(pos) individuals was associated with a decreased relative redeployment of the CD158a+ and CD57+ NK-cell subsets in younger and older individuals. In addition, we show that aging is associated with a CMV-independent increase in the proportion of NK-cells expressing the terminal differentiation marker CD57, while CMV is associated with an age-dependent decrease in the proportion of NK-cells expressing the inhibitory receptors KLRG1 (in the younger group) and CD158a (in the older group). Collectively, these data suggest that CMV may decrease NK-cell mediated immunosurveillance after exercise in both younger and older individuals.
• Fiuza-Luces, C., Garatachea, N., Simpson, R. J., Berger, N. A., Ramírez, M., & Lucia, A. (2015). Understanding graft-versus-host disease. Preliminary findings regarding the effects of exercise in affected patients. Exercise immunology review, 21, 80-112.
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  Advances in this century regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) have led to an expanding population of long-term survivors, many of whom suffer severe side effects, particularly those related to graft-versushost disease (GVHD), a potentially multi-systemic disorder caused by immunoeffector donor lymphocytes that destroy host tissues. The GVHD, especially in its chronic form (cGVHD), generates considerable morbidity and compromises the physical capacity of patients. We have reviewed the main pathophysiological aspects of the disease as well as the data available on the effects of exercise in GVHD, based on animal and human patient research. Although exercise training as an adjunct therapy to improve health outcomes after allo-HSCT shows promise (particularly, this lifestyle intervention can improve physical fitness and possibly immune function while attenuating fatigue), there is a need for more randomized control trials that focus specifically on GVHD.
• Ingram, L. A., Simpson, R. J., Malone, E., & Florida-James, G. D. (2015). Sleep disruption and its effect on lymphocyte redeployment following an acute bout of exercise. Brain, behavior, and immunity, 47, 100-8.
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  Sleep disruption and deprivation are common in contemporary society and have been linked with poor health, decreased job performance and increased life-stress. The rapid redeployment of lymphocytes between the blood and tissues is an archetypal feature of the acute stress response, but it is not known if short-term perturbations in sleep architecture affect lymphocyte redeployment. We examined the effects of a disrupted night sleep on the exercise-induced redeployment of lymphocytes and their subtypes. 10 healthy male cyclists performed 1h of cycling at a fixed power output on an indoor cycle ergometer, following a night of undisrupted sleep (US) or a night of disrupted sleep (DS). Blood was collected before, immediately after and 1h after exercise completion. Lymphocytes and their subtypes were enumerated using direct immunofluorescence assays and 4-colour flow cytometry. DS was associated with elevated concentrations of total lymphocytes and CD3(-)/CD56(+) NK-cells. Although not affecting baseline levels, DS augmented the exercise-induced redeployment of CD8(+) T-cells, with the naïve/early differentiated subtypes (KLRG1(-)/CD45RA(+)) being affected most. While the mobilisation of cytotoxic lymphocyte subsets (NK cells, CD8(+) T-cells γδ T-cells), tended to be larger in response to exercise following DS, their enhanced egress at 1h post-exercise was more marked. This occurred despite similar serum cortisol and catecholamine levels between the US and DS trials. NK-cells redeployed with exercise after DS retained their expression of perforin and Granzyme-B indicating that DS did not affect NK-cell 'arming'. Our findings indicate that short-term changes in sleep architecture may 'prime' the immune system and cause minor enhancements in lymphocyte trafficking in response to acute dynamic exercise.
• LaVoy, E. C., Bollard, C. M., Hanley, P. J., Blaney, J. W., O'Connor, D. P., Bosch, J. A., & Simpson, R. J. (2015). A single bout of dynamic exercise enhances the expansion of MAGE-A4 and PRAME-specific cytotoxic T-cells from healthy adults. Exercise immunology review, 21, 144-53.
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  The ex vivo expansion of tumor-associated-antigen (TAA)- specific cytotoxic T-cells (CTLs) from healthy donors for adoptive transfer to cancer patients is now providing additional treatment options for patients. Many studies have shown that adoptive transfer of expanded CTLs can reduce the risk of relapse in cancer patients following hematopoietic stem cell transplantation (HSCT). However, the procedure can be limited by difficulties in priming and expanding sufficient numbers of TAA-specific-CTLs. Because acute dynamic exercise mobilizes large numbers of T-cells to peripheral blood, we hypothesized that a single bout of exercise would augment the ex vivo expansion of TAA-specific-CTLs.We therefore collected lymphocytes from blood donated by healthy adults at rest and after brief maximal dynamic exercise. TAA-specific CTLs were expanded using autologous monocyte-derived-dendritic cells pulsed with melanoma-associated antigen 4 (MAGE-A4), with preferentially expressed antigen in melanoma (PRAME), and with Wilms' tumor protein (WT-1). Post exercise, 84% of the participants had a greater number of CTLs specific for at least one of the three TAA.Cells expanded from post exercise blood yielded a greater number of MAGE-A4 and PRAME-specific-cells in 70% and 61% of participants, respectively. In the 'exercise-responsive' participants (defined as participants with at least a 10% increase in TAA-specific-CTLs post-exercise), MAGEA4- and PRAME-specific-CTLs increased 3.4-fold and 6.2- fold respectively. Moreover, expanded TAA-specific CTLs retained their antigen-specific cytotoxic activity. No phenotype differences were observed between expanded cells donated at rest and postexercise. We conclude that exercise can enhance the ex vivo expansion of TAA-specific-CTLs from healthy adults without compromising cytotoxic function. Hence, this study has implications for immunotherapy using adoptive T-cell transfer of donor-derived T-cells after allogeneic HSCT.
• LaVoy, E. C., Bollard, C. M., Hanley, P. J., O'Connor, D. P., Lowder, T. W., Bosch, J. A., & Simpson, R. J. (2015). A single bout of dynamic exercise by healthy adults enhances the generation of monocyte-derived-dendritic cells. Cellular immunology, 295(1), 52-9.
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  The ex vivo generation of monocyte-derived-dendritic cells (mo-DCs) has facilitated the use of DCs in immunotherapy research. However, low blood monocyte numbers frequently limit the manufacture of sufficient numbers of mo-DCs for subsequent experimental and clinical procedures. Because exercise mobilizes monocytes to the blood, we tested if acute dynamic exercise by healthy adults would augment the generation of mo-DCs without compromising their differentiation or function. We compared mo-DC generation from before- and after-exercise blood over 8-days of culture. Function was assessed by FITC-dextran uptake and the stimulation of autologous cytomegalovirus (pp65)-specific-T-cells. Supporting the hypothesis, we found a near fourfold increase in number of mo-DCs generated after-exercise. Furthermore, relative FITC-dextran uptake, differentiation rate, and stimulation of pp65-specific-T-cells did not differ between before- and after-exercise mo-DCs. We conclude that exercise enhances the ex vivo generation of mo-DCs without compromising their function, and so may overcome some limitations associated with manufacturing these cells for immunotherapy.
• Pollonini, L., Padhye, N. S., Re, R., Torricelli, A., Simpson, R. J., & Dacso, C. C. (2015). Pulse transit time measured by photoplethysmography improves the accuracy of heart rate as a surrogate measure of cardiac output, stroke volume and oxygen uptake in response to graded exercise. Physiological measurement, 36(5), 911-24.
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  Heart rate (HR) is a valuable and widespread measure for physical training programs, although its description of conditioning is limited to the cardiac response to exercise. More comprehensive measures of exercise adaptation include cardiac output (Q̇), stroke volume (SV) and oxygen uptake (V̇O2), but these physiological parameters can be measured only with cumbersome equipment installed in clinical settings. In this work, we explore the ability of pulse transit time (PTT) to represent a valuable pairing with HR for indirectly estimating Q̇, SV and V̇O2 non-invasively. PTT was measured as the time interval between the peak of the electrocardiographic (ECG) R-wave and the onset of the photoplethysmography (PPG) waveform at the periphery (i.e. fingertip) with a portable sensor. Fifteen healthy young subjects underwent a graded incremental cycling protocol after which HR and PTT were correlated with Q̇, SV and V̇O2 using linear mixed models. The addition of PTT significantly improved the modeling of Q̇, SV and V̇O2 at the individual level ([Formula: see text] for SV, 0.548 for Q̇, and 0.771 for V̇O2) compared to predictive models based solely on HR ([Formula: see text] for SV, 0.503 for Q̇, and 0.745 for V̇O2). While challenges in sensitivity and artifact rejection exist, combining PTT with HR holds potential for development of novel wearable sensors that provide exercise assessment largely superior to HR monitors.
• Simpson, R. J. (2015). Fitness deficits in long-term ALL survivors. Blood, 125(22), 3366-8.
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  In this issue of Blood, Ness et al report that, despite the omission of prophylactic cranial radiotherapy (CRT) in the treatment of acute lymphoblastic leukemia (ALL), adult survivors of childhood ALL remain at risk for impaired fitness, body composition, and energy balance.
• Simpson, R. J., Kunz, H., Agha, N., & Graff, R. (2015). Exercise and the Regulation of Immune Functions. Progress in molecular biology and translational science, 135, 355-80.
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  Exercise has a profound effect on the normal functioning of the immune system. It is generally accepted that prolonged periods of intensive exercise training can depress immunity, while regular moderate intensity exercise is beneficial. Single bouts of exercise evoke a striking leukocytosis and a redistribution of effector cells between the blood compartment and the lymphoid and peripheral tissues, a response that is mediated by increased hemodynamics and the release of catecholamines and glucocorticoids following the activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. Single bouts of prolonged exercise may impair T-cell, NK-cell, and neutrophil function, alter the Type I and Type II cytokine balance, and blunt immune responses to primary and recall antigens in vivo. Elite athletes frequently report symptoms associated with upper respiratory tract infections (URTI) during periods of heavy training and competition that may be due to alterations in mucosal immunity, particularly reductions in secretory immunoglobulin A. In contrast, single bouts of moderate intensity exercise are "immuno-enhancing" and have been used to effectively increase vaccine responses in "at-risk" patients. Improvements in immunity due to regular exercise of moderate intensity may be due to reductions in inflammation, maintenance of thymic mass, alterations in the composition of "older" and "younger" immune cells, enhanced immunosurveillance, and/or the amelioration of psychological stress. Indeed, exercise is a powerful behavioral intervention that has the potential to improve immune and health outcomes in the elderly, the obese, and patients living with cancer and chronic viral infections such as HIV.

Proceedings Publications

• Cho, D., Basen-Engquist, K., Simpson, R., Ma, H., Pettaway, C., Li, Y., Canfield, S., Carmack, C., Davis, J., Jones, J., & others, . (2020). Watchful Living: A pilot lifestyle intervention for African American and Hispanic prostate cancer patients on active surveillance and their partners. In CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, 29.
• Gustafson, M., Wheatley-Guy, C., Bornschlegl, S., Dietz, A., Gastineau, D., Katsanis, E., Simpson, R., & Johnson, B. (2019). Physical fitness influences the composition of human T cell populations. In JOURNAL FOR IMMUNOTHERAPY OF CANCER, 7.

Presentations

• Simpson, R. (2018, February). NK-CELL FUNCTION IS IMPAIRED DURING LONG-DURATION SPACEFLIGHT: IMPACT OF 6 AND 12-MONTH MISSIONS TO THE ISS. NASA Investigators Workshop. Galveston, TX: NASA Human Research Program.

Reviews

• Filioglou, D., Husnain, M., Khurana, S., Simpson, R. J., & Katsanis, E. (2023. Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?(p. 1329850).
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  The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.

Others

• Cho, D., Basen-Engquist, K., Simpson, R., Ma, H., Pettaway, C., Li, Y., Canfield, S., Carmack, C., Davis, J., Jones, J., & others, . (2020). Abstract A053: Watchful Living: A pilot lifestyle intervention for African American and Hispanic prostate cancer patients on active surveillance and their partners.
• Dietz, J. R., Moran, M. S., Isakoff, S. J., Kurtzman, S. H., Willey, S. C., Burstein, H. J., Bleicher, R. J., Lyons, J. A., Sarantou, T., Baron, P. L., & others, . (2020). Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. the COVID-19 pandemic breast cancer consortium.