- Associate Professor, Nutritional Sciences
- Associate Professor, Pediatrics
- Associate Professor, Physiological Sciences - GIDP
- Associate Professor, Cancer Biology - GIDP
- Associate Professor, Immunobiology
- Associate Professor, BIO5 Institute
- Presidential Election
- International Society of Exercise Immunology (ISEI), Fall 2019
- American Physiological Society Select
- American Physiological Society, Spring 2019
- University of Houston Award for Achievements in Research and Scholarship (Associate Professor Rank)
- University of Houston, Spring 2017
- Fellowship of the American College of Sports Medicine
- American College of Sports Medicine, Spring 2014
No activities entered.
Bioenergetics & MetabolismNSC 608 (Fall 2020)
Independent StudyNSC 699 (Fall 2020)
ResearchPS 900 (Fall 2020)
ResearchPS 900 (Spring 2020)
Rsrch Meth Psio SciPS 700 (Spring 2020)
ThesisNSC 910 (Spring 2020)
Cellular+Molecular PsioPSIO 503 (Fall 2019)
Independent StudyNSC 699 (Fall 2019)
Introduction to ResearchMCB 795A (Fall 2019)
ResearchPS 900 (Fall 2019)
Directed ResearchPSIO 492 (Spring 2019)
Honors ThesisPSIO 498H (Spring 2019)
Independent StudyNSC 699 (Spring 2019)
Introduction to ResearchMCB 795A (Spring 2019)
Rsrch Meth Psio SciPS 700 (Spring 2019)
Bioenergetics & MetabolismNSC 608 (Fall 2018)
Directed ResearchPSIO 492 (Fall 2018)
Honors ThesisPSIO 498H (Fall 2018)
Introduction to ResearchMCB 795A (Fall 2018)
Directed ResearchPSIO 492 (Spring 2018)
- 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.More infoLatent 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.
- 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 Î²-Adrenergic Receptor Activation Augments the ex vivo Expansion and Anti-Tumor Activity of VÎ³9VÎ´2 T-Cells. Frontiers in Immunology, 10, 3082.
- 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).More infoAs 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.
- 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.More infoThe 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.More infoRemodelling 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.More infoDesigned 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.
- 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.
- 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.More infoAcute 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).More infoMaintaining 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.More infoCytomegalovirus (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.More infoRecent 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.More infoAcute 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.More infoAdoptive 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.More infoGuidelines 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.More infoAcute 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.More infoAging 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).More infoLong 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.More infoAlthough 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).More infoThe 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.More infoThe 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.More infoHigh 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.More infoRawcliffe, 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.More infoHematopoietic 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.More infoWe 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.More infoCytomegalovirus (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.More infoCMV 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.More infoAllogeneic 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.More infoAfrican 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.More infoHuman 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.More infoCytomegalovirus (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.More infoThe 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.More infoNatural 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.More infoThe 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.More infoAdvances 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.More infoSleep 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.More infoThe 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.More infoThe 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.More infoHeart 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.More infoIn 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.More infoExercise 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.
- 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.