The Influence of Sex, Training Status, and Fatty Acid Supplementation on T-lymphocyte Populations at Rest and in Response to Acute Exercise.

This series of studies began with an examination of the effects of training status (Tr vs UTr) and sex on the resting levels and redistribution of senescent (CD28-CD57+) and naïve (CD28+CD57-) T-lymphocytes (CD4+, CD8+) following a treadmill test to volitional exhaustion. In this first study exercise elicited a redistribution of senescent CD4+, CD8+ and naïve CD4+,CD8+ T-lymphocytes. UTr had a higher proportion of senescent and a lower proportion of naïve CD8+ T-lymphocytes than Tr. Males had a higher proportion of senescent and lower proportion of naïve T-lymphocytes than females with the highest percentage of senescent and lowest percentage of naïve T-lymphocytes observed in UTr males. CMV was a covariate in the senescent and naïve CD8+ T-lymphocytes. This study highlighted important sex and training status differences in the senescent and naïve T-lymphocyte redistribution in response to exercise. These findings led on to an investigation of the T-lymphocyte (CD4+, CD8+, γδ+) response to a period of 2 weeks increased volume training (39% increase in volume) in trained females (Tr, n=13) compared to a period of 2 weeks habitual activity in female controls (UTr, n=13). This second study observed no difference in the resting T-lymphocyte profile from the pre to post increased volume training period. The resting number of CD3+ and proportion of γδ+ T-lymphocytes was greater in the Tr compared to the UTr. The resting proportion of CD4+T-lymphocytes and the CD4+:CD8+ ratio was greater in the UTr compared to the Tr. CMV was a covariate in the analysis of CD8+, CD28+ CD8+, and naïve CD8+ T-lymphocyte cell numbers but not in the analysis of T-lymphocyte proportions. The increased volume training period had no effect on resting T-lymphocyte populations in Tr females, and T-lymphocyte populations also did not change with 2 weeks of habitual exercise in UTr. The total energy, carbohydrate and protein intake was greater in Tr compared to the UTr during the increased volume training period and was greater than normal in the Tr group. These dietary influences may partly explain the absence of any change in T-lymphocyte proportions pre to post training period in Tr. Differences in the proportions of γδ+, CD4+ and the ratio of CD4+:CD8+ T-lymphocytes at rest between the Tr and UTr warrants further investigation. The final study of this series is presented in two parts. The first part focused on the influence of 4 weeks supplementation at 0.1g/kg body mass/day with n-3 polyunsaturated fatty acids (PUFA) as fish oil (FO, n=10), or short-chain saturated fatty acids (SFA) as coconut oil (CO, n=10) on T-lymphocyte (CD4+,CD8+, γδ+) differentiated populations at rest and in response to exercise in trained males. Changes were examined by Day (Baseline to pre supplementation, Pre Sup (4 week control period), and pre supplementation to post supplementation, Post Sup (4 week supplementation period)). During a 4 week baseline control period no changes were observed in the blood lipid profile in both FO and CO groups. During the control period a main effect of exercise was observed in all the CD3+ and γδ+ T-lymphocytes subsets. During the control period an interaction of group-by-day was observed in the senescent CD8+ T-lymphocytes from BL to Pre Sup the proportion and number decreased in the FO group and increased in the CO group. Inclusion of CMV as a covariate introduced a main effect of group on the CD4+ naïve proportions and cell counts and the group-by-day interaction observed on the CD8+ senescent T-lymphocyte proportions and cell counts disappeared. During the 4 week supplementation period this study observed an increase in the n-3 PUFAs, EPA (20:5n-3), DHA (22:6n-3) and DPA (22:5n-3) in the FO group but not in the CO group (with no changes in blood lipid profile on CO). During the supplementation period a main effect of exercise was observed in all the CD3+ and γδ+ T-lymphocyte subsets except for the proportion of CD8+ naïve T-lymphocytes. The proportion of CD8+ naïve T-lymphocytes was lower at rest and in response to exercise in FO and CO groups after supplementation. CMV was a significant covariate in senescent CD4+ T-lymphocyte cell counts. At the post exercise time point the γδ+ T-lymphocyte count increased in the FO group but decreased in the CO group, following the supplementation period. However, this observation did not quite reach statistical significance. Although a difference between the groups was evident for γδ+ T-lymphocyte count and proportion there was insufficient evidence to conclude whether the difference was supplement related. It would appear that dose, duration and type of fatty acids ingested could all be important in the overall response but these require further study. The second part of this final study investigated the influence of 4 week supplementation at 0.1g/kg body mass/day with n-3 polyunsaturated fatty acids (PUFA) as fish oil (FO, n=10) or short-chain saturated fatty acids (SFA) as coconut oil (CO, n=10) on plasma Th1 cytokine: IL-2, TNF- α and IFN-γ, and Th2 cytokine IL-4, IL-6 and IL-10 concentrations, and expression of the T-lymphocyte activation marker CD69 at rest and in response to exercise in trained males. Changes were examined by Day (Baseline to pre supplementation (4 week control period), and pre supplementation to post supplementation (4 week supplementation period)). This study observed an increase in n-3 PUFAs, EPA (20:5n-3), DHA (22:6n-3) and DPA (22:5n-3) in the FO group but not in the CO group. There was a significant mobilisation of activated CD4+ CD69+ and CD8+ CD69+ (P<0.05) T-lymphocyte numbers in response to exercise in both FO and CO groups. CMV infection was a significant covariate on the number and proportion of CD4+CD69+ T-lymphocytes (P<0.05) but not on the number or proportion of CD8+CD69+ T-lymphocytes. During the supplementation period there was a significant effect of Day on TNF-α, IL-6, IL-4 and IL-2 with IFN-γ and IL-10 trending towards a difference. The plasma cytokine concentration was greater at post supplementation compared to pre supplementation for both FO and CO groups. Latent CMV infection was a significant covariate for TNF-α, IL-6, IL-4, IL-2, IFN-γ and IL-10. In the current study we observed no evidence of a difference between the CO and FO groups for early T-lymphocyte activation marker or plasma cytokine concentrations despite the membrane lipid composition change over the 4 week supplementation period. It would appear that the plasma Th1 and Th2 cytokine concentration increased from pre supplementation to post supplementation on both PUFA and SFA, highlighting a potential link between fatty acid incorporation and cytokine expression that needs closer examination. The results of this series of studies highlight that sex and training status impact upon the T-lymphocyte pool at rest and in response to exercise. Increasing the volume of training for 2 weeks without dietary restriction does not alter the resting T-lymphocyte pool in trained females. Alterations to the T-lymphocyte pool at rest and in response to exercise are not related to FO or CO supplementation. Furthermore, the response of Th1, Th2 plasma cytokines, and the early activation marker CD69 at rest and in response to exercise does not differ between a group supplemented with FO compared to a group supplemented with CO it would appear that Th1 and Th2 plasma cytokines increase post supplementation in both groups. Particular avenues of interest for future research would be, to explore the sex differences in T-lymphocyte subsets at rest and in response to exercise, to determine whether these sex differences are key in susceptibility to disease/infection and to determine the tissue targets of lymphocytes mobilised during exercise

Harnessing the immunomodulatory effects of exercise to enhance the efficacy of monoclonal antibody therapies against B-cell haematological cancers: a narrative review

Therapeutic monoclonal antibodies (mAbs) are standard care for many B-cell haematological cancers. The modes of action for these mAbs include: induction of cancer cell lysis by activating Fcγ-receptors on innate immune cells; opsonising target cells for antibody-dependent cellular cytotoxicity or phagocytosis, and/or triggering the classical complement pathway; the simultaneous binding of cancer cells with T-cells to create an immune synapse and activate perforin-mediated T-cell cytotoxicity against cancer cells; blockade of immune checkpoints to facilitate T-cell cytotoxicity against immunogenic cancer cell clones; and direct delivery of cytotoxic agents via internalisation of mAbs by target cells. While treatment regimens comprising mAb therapy can lead to durable anti-cancer responses, disease relapse is common due to failure of mAb therapy to eradicate minimal residual disease. Factors that limit mAb efficacy include: suboptimal effector cell frequencies, overt immune exhaustion and/or immune anergy, and survival of diffusely spread tumour cells in different stromal niches. In this review, we discuss how immunomodulatory changes arising from exposure to structured bouts of acute exercise might improve mAb treatment efficacy by augmenting (i) antibody-dependent cellular cytotoxicity, (ii) antibody-dependent cellular phagocytosis, (iii) complement-dependent cytotoxicity, (iv) T-cell cytotoxicity, and (v) direct delivery of cytotoxic agents

Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy <i>in vitro</i>

Multiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for ∼30-minutes, with blood samples collected pre-, immediately post-, and 30-minutes post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively (p &lt; 0.001), owing to an increased frequency of CD3−CD56+CD16+ NK-cells (+348%), HLA-DR+CD14dimCD16+ monocytes (+125%), and HLA-DR+CD14+CD32+ monocytes (+41%) in blood (p &lt; 0.01). However, overall, total plasma cells (CD38+CD138+) nor clonal plasma cells (CD38brightCD138+CD45−/dimCD19− with light-chain restriction) increased in blood (p &gt; 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide – whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro. However, plasma cells were largely unchanged, and NK-cells expressing CD38 – the daratumumab target antigen – increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis

‘You’re kind of left to your own devices’: a qualitative focus group study of patients with breast, prostate or blood cancer at a hospital in the South West of England, exploring their engagement with exercise and physical activity during cancer treatment and in the months following standard care

Objectives: The aim of this study was to explore the experiences of patients with breast, prostate or blood cancer, regarding their (1) engagement with exercise and physical activity during treatment and in the months following standard care, and (2) the meanings attached to these lifestyle behaviours.Design: A qualitative study using focus groups. The groups were audio recorded, transcribed and analysed using Framework analysis.Setting: A hospital-based cancer treatment centre in the South-West of England.Participants: Eighteen people who had either completed treatment or were currently on maintenance therapy for breast, prostate or blood cancer (non‐Hodgkin lymphoma or Hodgkin lymphoma).Results: Participants reported treatment limiting their ability to engage in exercise and physical activity. However, participants were aware of the physiological, emotional and social benefits of exercise and expressed a desire to maintain a physically active lifestyle before, during and after treatment. They noted a lack of concrete guidance and appropriate exercise classes for people with cancer and felt poorly informed about the type, intensity, duration and frequency of exercise they should be undertaking. As such, participants reported making decisions on their own, relying on their intuition and listening to their bodies to gauge whether they were doing enough exercise (or not).Conclusions: Participants were aware of the benefits of a physically active lifestyle during and following cancer treatment, but were not familiar with exercise and physical activity guidelines for people living with and beyond cancer. There is a need for healthcare professionals, academics and policy makers to determine how exercise and physical activity can be supported in clinical settings in realistic and meaningful ways accommodating individual patient circumstances

‘You’re kind of left to your own devices’: a qualitative focus group study of patients with breast, prostate or blood cancer at a hospital in the South West of England, exploring their engagement with exercise and physical activity during cancer treatment and in the months following standard care

Objectives: The aim of this study was to explore the experiences of patients with breast, prostate or blood cancer, regarding their (1) engagement with exercise and physical activity during treatment and in the months following standard care, and (2) the meanings attached to these lifestyle behaviours.Design: A qualitative study using focus groups. The groups were audio recorded, transcribed and analysed using Framework analysis.Setting: A hospital-based cancer treatment centre in the South-West of England.Participants: Eighteen people who had either completed treatment or were currently on maintenance therapy for breast, prostate or blood cancer (non‐Hodgkin lymphoma or Hodgkin lymphoma).Results: Participants reported treatment limiting their ability to engage in exercise and physical activity. However, participants were aware of the physiological, emotional and social benefits of exercise and expressed a desire to maintain a physically active lifestyle before, during and after treatment. They noted a lack of concrete guidance and appropriate exercise classes for people with cancer and felt poorly informed about the type, intensity, duration and frequency of exercise they should be undertaking. As such, participants reported making decisions on their own, relying on their intuition and listening to their bodies to gauge whether they were doing enough exercise (or not).Conclusions: Participants were aware of the benefits of a physically active lifestyle during and following cancer treatment, but were not familiar with exercise and physical activity guidelines for people living with and beyond cancer. There is a need for healthcare professionals, academics and policy makers to determine how exercise and physical activity can be supported in clinical settings in realistic and meaningful ways accommodating individual patient circumstances

Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy in vitro

Multiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for ∼30-minutes, with blood samples collected pre-, immediately post-, and 30-minutes post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively (p &lt; 0.001), owing to an increased frequency of CD3−CD56+CD16+ NK-cells (+348%), HLA-DR+CD14dimCD16+ monocytes (+125%), and HLA-DR+CD14+CD32+ monocytes (+41%) in blood (p &lt; 0.01). However, overall, total plasma cells (CD38+CD138+) nor clonal plasma cells (CD38brightCD138+CD45−/dimCD19− with light-chain restriction) increased in blood (p &gt; 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide – whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro. However, plasma cells were largely unchanged, and NK-cells expressing CD38 – the daratumumab target antigen – increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Acute aerobic exercise induces a preferential mobilisation of plasmacytoid dendritic cells into the peripheral blood in man.

Dendritic cells (DCs) are important sentinel cells of the immune system responsible for presenting antigen to T cells. Exercise is known to cause an acute and transient increase in the frequency of DCs in the bloodstream in humans, yet there are contradictory findings in the literature regarding the phenotypic composition of DCs mobilised during exercise, which may have implications for immune regulation and health. Accordingly, we sought to investigate the composition of DC sub-populations mobilised in response to acute aerobic exercise. Nine healthy males (age, 21.9 ± 3.6 years; height, 177.8 ± 5.4 cm; body mass, 78.9 ± 10.8 kg; body mass index, 24.9 ± 3.3 kg·m 2; V̇O 2 MAX, 41.5 ± 5.1 mL·kg·min −1) cycled for 20 min at 80% V̇O 2 MAX. Blood was sampled at baseline, during the final minute of exercise and 30 min later. Using flow cytometry, total DCs were defined as Lineage− (CD3, CD19, CD20, CD14, CD56) HLA-DR+ and subsequently identified as plasmacytoid DCs (CD303+) and myeloid DCs (CD303−). Myeloid DCs were analysed for expression of CD1c and CD141 to yield four sub-populations; CD1c−CD141+; CD1c+CD141+; CD1c+CD141− and CD1c−CD141−. Expression of CD205 was also analysed on all DC sub-populations to identify DCs capable of recognising apoptotic and necrotic cells. Total DCs increased by 150% during exercise (F (1,10) = 60; p &lt; 0.05, η 2 = 0.9). Plasmacytoid DCs mobilised to a greater magnitude than myeloid DCs (195 ± 131% vs. 131 ± 100%; p &lt; 0.05). Among myeloid DCs, CD1c−CD141− cells showed the largest exercise-induced mobilisation (167 ± 122%), with a stepwise pattern observed among the remaining sub-populations: CD1c+CD141− (79 ± 50%), followed by CD1c+CD141+ (44 ± 41%), with the smallest response shown by CD1c−CD141+ cells (23 ± 54%) (p &lt; 0.05). Among myeloid DCs, CD205− cells were the most exercise responsive. All DC subsets returned to resting levels within 30 min of exercise cessation. These results show that there is a preferential mobilisation of plasmacytoid DCs during exercise. Given the functional repertoire of plasmacytoid DCs, which includes the production of interferons against viral and bacterial pathogens, these findings indicate that exercise may augment immune-surveillance by preferentially mobilising effector cells; these findings have general implications for the promotion of exercise for health, and specifically for the optimisation of DC harvest for cancer immunotherapy. </p

n-3 Fatty Acid Supplementation During 4 Weeks of Training Leads to Improved Anaerobic Endurance Capacity, but not Maximal Strength, Speed, or Power in Soccer Players

Omega-3 fatty acid (n-3 FA) supplementation could promote adaptation to soccer-specific training. We examined the impact of a 4-week period of n-3 FA supplementation during training on adaptations in 1RM knee extensor strength, 20-m sprint speed, vertical jump power, and anaerobic endurance capacity (Yo-Yo test) in competitive soccer players. Twenty six soccer players were randomly assigned to one of two groups: n-3 FA supplementation (n-3 FA; n = 13) or placebo (n = 13). Both groups performed two experimental trial days. Assessments of physical function and respiratory function were conducted pre (PRE) and post (POST) supplementation. Training session intensity, competitive games and nutritional intake were monitored during the 4-week period. No differences were observed in respiratory measurements (FEV1, FVC) between groups. No main effect of treatment was observed for 1RM knee extensor strength, explosive leg power, or 20 m sprint performance, but strength improved as a result of the training period in both groups (p < .05). Yo-Yo test distance improved with training in the n-3 FA group only (p < .01). The mean difference (95% CI) in Yo-Yo test distance completed from PRE to POST was 203 (66–340) m for n-3 FA, and 62 (-94–217) m for placebo, with a moderate effect size (Cohen’s d of 0.52). We conclude that 4 weeks of n-3 FA supplementation does not improve strength, power or speed assessments in competitive soccer players. However, the increase in anaerobic endurance capacity evident only in the n-3 FA treatment group suggests an interaction that requires further study