Thomas Lowder

Exercise-induced modulation of macrophage function

Macrophages are important effector cells involved in phagocytosis, microbial killing and antitumour activity. Macrophages also display accessory cell function, in that they can present antigen to foster the development of T lymphocyte‐mediated immunity. Recent work, including studies from this group, has demonstrated that acute and chronic exercise can affect many facets of macrophage biology. Manifestation of these effects depends on exercise intensity and duration, the function measured, the timing of measurement in relation to exercise and the concentration of the macrophage‐activating stimulus. Exercise has potent stimulatory effects on phagocytosis, antitumour activity, reactive oxygen and nitrogen metabolism, and chemotaxis. Indeed, it has been shown that exercise training can increase macrophage antitumour activity in mice of different ages. However, not all functions are enhanced by exercise. Exercise‐induced reductions in macrophage MHC II expression and antigen‐presentation capacity have been documented. These findings bring up the possibility that exercise, and perhaps other stressors, activate macrophages for effector functions while downregulating accessory cell functions. To a large extent, the mechanisms responsible for the exercise‐induced changes in macrophage function remain unknown, but may depend on exercise‐induced changes in neuroendocrine factors. Future studies need to explore the effects in a mechanistic way and provide documentation as to their physiological significance.

Moderate exercise protects mice from death due to influenza virus

We wanted to determine if different doses of exercise, performed in the initial days after infection when the host is mounting an immune response, altered mortality, and morbidity to influenza virus infection in mice. Forty hemagglutinating units of influenza virus (A/Puerto Rico/8/34) were administered intranasally to lightly anesthetized mice. Male Balb/cByJ mice were randomized to one of three groups: sedentary control (CON); moderate (MOD) exercise (20-30 min at 8-12 m/min); or prolonged (PRO) exercise (2.5 h at 8-12 m/min). Mice exercised on a treadmill 4 h post-infection and for three more consecutive days before symptom onset. Mortality, morbidity, bodyweight, and food intake were assessed. MOD had a significantly (p = .007) higher survival (18 of 22; 82%) rate when compared to CON (10 of 23; 43%). There was no difference in morbidity between MOD and CON, despite improved survival. PRO exhibited a survival rate of 30% (p = .29 vs. CON) and demonstrated significantly higher morbidity on several days. While all groups exhibited anorexia and significant body weight loss (approximately 30-35%) post-infection, exercise had little effect on these variables. We demonstrate that moderate exercise, performed in the initial days after influenza infection, significantly decreased mortality in mice. Prolonged exercise led to increased morbidity and tended to decrease survival.

Cardiovascular exercise training extends influenza vaccine seroprotection in sedentary older adults: the immune function intervention trial.

OBJECTIVES: To determine whether cardiovascular exercise training resulted in improved antibody responses to influenza vaccination in sedentary elderly people who exhibited poor vaccine responses.

Can exercise training improve immune function in the aged

Many strategies have been used to improve immune function in the aged. Unfortunately, many of these interventions have been disappointing, impractical, costly to develop and administer, or accompanied by adverse side effects. Aside from dietary manipulation (caloric restriction without malnutrition or antioxidant supplementation), research involving behavioral preventative or restorative therapies has been lacking. Moderate exercise training has been shown to elicit beneficial outcomes in both the prevention and rehabilitation of many diseases of the elderly. It has been hypothesized that moderate levels of exercise improves, whereas strenuous exercise or overtraining suppresses, various immune function measures. Three general approaches have been implemented to study the impact of exercise on immune functioning in the elderly: (1) cross‐sectional studies, (2) longitudinal studies, and (3) animal studies. In general, cross‐sectional studies examining highly active elderly have demonstrated improved in vitro T cell responses to polyclonal stimulation when compared to sedentary elderly. This is corroborated by several animal studies that have shown improved splenic T cell responses in vitro. Unfortunately, human prospective studies have failed to demonstrate consistent improvements in various measures of immune function in older adults. However, it should be cautioned that these studies have included small samples followed over a short duration, measuring a limited number of in vitro immune parameters, with some failing to account for potential confounding influences. Although such findings have the potential to be of substantial public health importance, very few systematic studies have been conducted.

Cardiovascular Exercise Intervention Improves the Primary Antibody Response to Keyhole Limpet Hemocyanin (KLH) in Previously Sedentary Older Adults

Based upon a prior cross-sectional study, we hypothesized that an aerobic exercise intervention in sedentary older adults would improve a primary T cell-dependent immune response. Participants were a subset of older subjects from a large, ongoing exercise intervention study who were randomly assigned to either an aerobic exercise (Cardio, n=30, 68.9+0.8 years) or flexibility/balance (Flex, n=20, 69.9+1.2 years) intervention. The intervention consisted of either three aerobic sessions for 30-60 min at 55-70% VO(2 max) or two 60 min flexibility/balance sessions weekly for 10 months. Eight months into the intervention, samples were collected before intramuscular administration of KLH (125 microg), followed by sampling at 2, 3, and 6 weeks post-KLH. Serum anti-KLH IgM, IgG1, and IgG2 was measured by ELISA. Physiological and psychosocial measures were also assessed pre- and post-intervention. While there was no difference in the anti-KLH IgG2 response between groups, Cardio displayed significantly (p<0.05) higher anti-KLH IgG1 (at weeks 2, 3, and 6 post) and IgM responses when compared to Flex. Despite cardiovascular intervention-induced improvement in physical fitness (approximately 11% vs. 1% change in VO(2 peak) in Cardio vs. Flex, respectively), we found no relationship between improved fitness and enhanced anti-KLH antibody responses. Optimism, perceived stress, and affect were all associated with enhanced immune response. We have shown for the first time that cardiovascular training in previously sedentary elderly results in significantly higher primary IgG1 and IgM antibody responses, while having no effect on IgG2 production.

Exercise training increases the näive to memory T cell ratio in old mice

Aging is associated with changes in T cells including involution of the thymus gland and an imbalance in the proportion of näive (CD44lo) and memory (CD44hi) T cells in the periphery. Reversal of these changes may improve immunity in the aged. We sought to determine whether 4 months of moderately intense treadmill running (EXC; 5 days/week, 45 min/day, 13-22 m/min) in 2 month (Y) and 18 month (O) old male Balb/c mice would alter T lymphocyte profiles in the thymus and spleen when compared to sedentary controls (CON). Splenocytes and thymocytes were harvested 24-48 h after the last exercise session and analyzed using immunofluorescence and flow cytometry. While there were significant age-related changes (lower cell number, altered subsets) in the thymuses of O when compared to Y mice, exercise training failed to affect any of these measures in mice of either age. Aged mice exhibited a significantly (p < .05) higher percentage of splenic memory cells and a lower percentage of näive cells in both the CD4 and CD8 T cell subsets. Interestingly, exercise training significantly (p < .05) increased the percentage of näive and decreased the percentage of memory cells in both the CD4+ (69.6+/-1.7% näive and 30.4+/-1.7% memory for OCON vs. 75.0+/-1.5% näive and 25.0+/-1.5% memory in OEXC) and CD8+ (60.0+/-2.6% näive and 40.0+/-2.6% memory in OCON vs. 76.7+/-2.7% näive and 23.3+/-2.7% memory in OEXC) T cells subsets in O, but not Y, mice. This effect was due to a decrease in the absolute number of memory cells and not an increase in the absolute number of näive cells. We conclude that 4 months of EXC has little restorative effect on the thymus in aged mice, but can restore the percentages of näive and memory cells in the spleen towards that of young mice, perhaps due to removal of memory cells.

Regulatory T Cells in Asthma and Airway Hyperresponsiveness

Regulatory T cells, or Tregs, have been shown to play a major role in reducing Th2 cell proliferation, potentially reducing (often significantly) airway-associated inflammation seen in airway diseases, such as asthma. These cells are characterized as a sub-population of T cells that maintain peripheral tolerance through a variety of biological mechanisms. Although Tregs make up only 5-10% of peripheral CD4 +

Relationship between Systemic Inflammation and Delayed-Type Hypersensitivity Response to Candida Antigen in Older Adults

Research has shown that aging is associated with increased systemic inflammation as well as a reduction in the strength of immune responses. However, little evidence exists linking the decrease in cell-mediated immunity in older adults with other health parameters. We sought to examine the relationship between cell-mediated immunity as measured in vivo by the delayed-type hypersensitivity (DTH) response to candida antigen and demographic and physiological variables in older (65–80 y.o.) adults. Candida antigen response was not related to gender or obesity, or to a number of other physiological variables including fitness and body composition. However, positive responders had significantly lower serum C-reactive protein levels (CRP, p<0.05) vs. non-responders. Furthermore, subjects with CRP<4.75 mg•L−1 had greater odds of developing a positive response compared to those with CRP>4.75 mg•L−1. Therefore, positive responses to candida antigen in older adults appears to be related to lower levels of systemic inflammation.

#89 The effects of exercise on lung IFN-γ, IL-10, and viral mRNA expression in adult mice

monocytes, lymphocytes, or neutrophils in the blood compared to untreated non-arthritic rats. Adrenergic drug treatments did not alter the total red blood cell counts in AA rat compared to untreated or vehicle-treated arthritic rats. Results from the toxicity panel were unremarkable for indexes of liver, kidney or cardiac toxicity, electrolyte balance, blood glucose levels, and cholesterol, calcium, and phosphorus values. Thus, these findings confirm and extend previous studies demonstrating the efficacy of these adrenergic treatments and provide initial toxicity studies, suggesting that adrenergic therapies aimed at b2-AR stimulation and a-AR blockade could be safe and beneficial for RA patients.