Vaccination is one of the most successful public health interventions in preventing infectious diseases and reducing the mortality and morbidity rates associated with these diseases. Chronically stressful situations can lead to reduced vaccine efficacy (1). Chronic stress suppresses immune function including both cell-mediated (as measured by the delayed-type hypersensitivity [DTH] response) and antibody responses to vaccination. Dhabhar and McEwen (2) has reported that chronic restraint stress for 6 h·d−1 for 3 to 5 wk significantly reduced DTH responses in rats, and increasing stress exposure was also associated with reduction of peripheral blood lymphocytes redistribution and decreased glucocorticoid responsivity. Other stressors, such as a social stressor, have also been shown to reduce antibody responses to vaccination in a rat model (3).
Exercise has been proposed to be an effective, cost-efficient behavioral intervention to enhance immune function and has a potential beneficial effect on immune responses to vaccination. Several human studies have suggested that acute eccentric exercise (ECC) enhances vaccination responses (4–6). Eccentric exercise causes the exercising muscle to produce continuous force while it lengthens, leading to damage of the internal structure of the muscle fibers and connective tissue (7). The substantial increase in plasma creatine kinase indicates this damage is greater than that caused by concentric or shortening muscle contractions (8). This muscle damage results in a localized inflammatory response and delayed onset muscle soreness when conducted in naive participants (9). It is hypothesized that the influx of immune cells and the release of inflammatory mediators caused by this eccentrically induced muscle damage creates a proinflammatory environment in a muscle that may activate dendritic and other cells to augment the immune response to vaccination when given intramuscularly (10). This heightened inflammatory environment may be a particularly effective adjuvant as eccentric exercise localizes muscle damage to the specific site of intramuscular (IM) vaccine administration.
Endurance exercise training has also been proven to augment either humoral or cell-mediated immunity to vaccination, especially in the elderly who exhibit poor vaccination response. Our laboratory has conducted two experiments comparing 10 months of moderate endurance exercise to flexibility/balance training in older adults (11,12). We found that cardiovascular exercise resulted in a longer-lasting seroprotection in response to influenza vaccination when measured 24 wk postvaccination, whereas flexibility/balance training did not (12). Similarly, aerobic exercise training induced higher primary IgG1 and IgM antibody responses to a primary immunogen when compared with the sedentary controls (11). However, not all studies have reported beneficial effects of exercise training in young and middle-age adults. Long et al. (13) showed a life-style physical activity intervention increased walking behavior and quality of life, but not antibody responses to pneumococcal vaccination compared to controls. In summary, aerobic exercise training has been shown to be beneficial in vaccine efficacy in the elderly (11,12), but not in the middle-age (13). These divergent findings could because the older adults have relative poor immune responses. Thus it is important to further examine the potentially beneficial role of endurance exercise training in an immunosuppressive setting.
Despite the potential beneficial role of ECC and endurance exercise training on immune responses to vaccination, the role exercise plays in attenuating stress-induced vaccine reduction is unknown. Moreover, the underlying mechanisms behind any exercise-induced beneficial effect remain understudied. Therefore, we used an animal model to develop further evidence for future study of potential mechanisms behind any exercise-induced augmentation of immune responses to vaccination in an immunosuppressive setting. The purpose of this study was to examine the effects of ECC and endurance exercise training on stress-induced attenuation of vaccination responses in mice. We used a novel benign protein antigen, ovalbumin (OVA), to investigate primary immune responses. We hypothesized that both ECC and endurance training would attenuate chronic stress-induced reductions in vaccination responses.
The study design can be found in Figure 1. To minimize preintervention differences in body weight, mice were randomized into four groups based on their baseline body weights. There were no significant differences in their baseline body weights among groups. A statistical power analysis, based on an expected 20% difference between groups with a power of 0.8 and α = 0.05, suggested that 12 mice per group were necessary to test the hypothesis. Mice were randomized into four groups: mice that did not receive restraint stress and were sedentary in their home cage (CON, n = 12), mice that received chronic restraint stress and performed a single ECC bout (S-ECC, n = 14), mice that received chronic restraint stress and performed voluntary wheel running (S-VWR, n = 14), and mice received chronic restraint stress and remained sedentary (S-SED, n = 15). Mice in the S-ECC group performed a single acute bout of eccentrically biased downhill running (described below) 42 h after the last stress session. Mice in the S-VWR group were housed in cages with free access to telemetered running wheels starting from the first day of chronic restraint stress, continuing throughout the entire experiment. Mice in the S-SED group were handled similarly and housed in the same room with the treadmill and wheel cages to control for incidental stress. Mice in the CON group stayed in their home cage for the entire experiment. All mice received an IM injection at 43 h after the first week’s stress session (immediately after eccentric exercise for S-ECC group). Two weeks after the sensitization, all mice were challenged with a subcutaneous injection to assess DTH responses. Body weight was measured immediate after stress daily. Mice were euthanized for tissue collection at 4 wk post-initial OVA sensitization.
C57BL/6J male mice age 6 to 8 wk (n = 55) were purchased from Jackson Laboratory (Bar Harbor, ME) and individually housed in our Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility. Mice were allowed ad libitum access to water and food (Teklad 8640; Harlan Laboratories, Indianapolis, IN). All animals were maintained on a reversed 12-h light–dark cycle. All experiments were approved by the University of Illinois at Urbana-Champaign Institutional Animal Care and Use Committee.
Chronic restraint stress
Chronic restraint stress was applied by placing mice in adequately ventilated 60-mL syringes while ensuring that they were capable of moving laterally, but not vertically. It has been shown that chronic restraint stress is widely used as a psychological stressor including activation of the autonomic nervous system, hypothalamic–pituitary–adrenal axis, and adrenal steroid receptors (14). Mice in the three chronic stress groups were exposed to the stressor 5 d·wk−1 for 6 h·d−1 for 3 wk. The chronic stress sessions were conducted from 9:00 AM to 3:00 PM Monday through Friday during the dark cycle (dark cycle: 3:00 AM to 3:00 PM).
Mice in S-ECC group were exercised at 17 m·min−1 speed at −20% grade for 45 min on a treadmill. No electrical shock was used. Lopez et al. (15) have shown this exercise protocol elicits muscle inflammation and significantly increases intracellular tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6), and interleukin-10 (IL-10). Mice were vaccinated in the gastrocnemius of their right hind limbs with OVA (Sigma-Aldrich, St. Louis, MO) immediately after exercise based on the study design of Edwards et al. (5) who demonstrated an eccentric-exercise induced benefit in influenza vaccine response in people.
Voluntary wheel running
All mice received an IM (Respironics, Bend, OR) during the entire experiment (other than restraint stress period). Mice in the other groups were housed in similar cages lacking the running wheel and were subjected to similar handling throughout the experiment. Average running distance was 3.91 ± 1.36 km·d−1.
In our experiments, all mice were intramuscularly inoculated in the gastrocnemius of their right hind limbs with 100 μg of OVA and 200 μg of alum in 50-μL sterile saline using a 25-g needle.
The DTH response measures the in vivo inflammatory reaction to a specific antigen. It has been shown that there is a positive relationship between the ear swelling and the ongoing cell-mediated immune response (16,17). Mice were injected with 100 μg OVA dissolved in 10-μL phosphate-buffered saline (PBS) into the dorsal side of the right ear using a Hilton syringed fitted with a 30-gauge needle on 21-d posteccentric exercise. The left ear received 10-μL PBS alone as a control for nonspecific ear swelling. The thickness of both ears was measured immediately before, and every 24 h after intradermal injection using a digital microcaliper (Tresna). The measurements were performed in triplicate by a research assistant who was blinded to the treatments. Results were expressed as the difference with preinjection ear thickness. Maximum ear swelling occurred on day 1 postear inoculation.
Before blood collection, mice were administered isoflurane with oxygen at a flow rate of 2 to 3 L·min−1 until unresponsive. All mice were bled approximately 200 μL from the retroorbital vein using a Pasteur pipette before vaccination and at 1, 2, and 4 wk postvaccination. Blood was dispensed into heparinized tubes and centrifuged at 1500g at 4°C for 15 min. Plasma was harvested and frozen at −20°C until analysis. At 4 wk postinoculation, mice were euthanized by CO2 asphyxiation followed by cervical dislocation, and blood was drawn after euthanasia from the inferior vena cava. Spleen and adrenal weights were also measured.
Plasma antibody measures
Plasma total anti-OVA IgG and anti-OVA IgM were determined using enzyme-linked immunosorbent assay procedures. Ninety-six-well microtiter plates were coated with 50 μL of 20 μg·mL−1 OVA in carbonate coating buffer and incubated overnight at 4°C. Nonspecific binding was blocked with PBS supplemented with 10% fetal bovine serum and incubated for 1 h at 37°C. After washing three times with PBS-Tween 20, 50 μL of plasma was added at a dilution of 1:20 (IgG) or 1:200 (IgM) in a diluting buffer of PBS/1% fetal bovine serum and incubated for 1 h at 37°C. Plates were washed again, and 50 μL of horseradish peroxidase-rabbit anti-mouse IgG or horseradish peroxidase-goat anti-mouse IgM (Life Technologies, Frederick, MD), diluted 1:800 or 1:400, respectively, in diluting buffer, was added. Plates were incubated again and then washed. Plates were incubated for 20 min in 50 μL of a 1:1 mixture of 3, 3′, 5,5′ tetramethylbenzidine (TMB) and hydrogen peroxide (TMB Substrate Reagent Set; BD Biosciences, San Jose, CA). Lastly, 25 μL of stop solution (sulfuric acid) was added, and plates were read at 450 nm on a spectrophotometric plate reader (Labsystems Multiskan; Fisher Scientific, Pittsburgh, PA). Plasma anti-OVA IgG or IgM was quantified as the difference in optical density at 450 nm from the preinjection time point.
Results were analyzed using SPSS 24.0 (SPSS Inc., Chicago, IL). Body weights, plasma anti-OVA IgG, anti-OVA IgM, and DTH responses were assessed by repeated-measures ANOVA. All analyses were followed by post hoc Bonferroni tests in the event of a significant main effect or interaction. Spleen and adrenal weights were assessed by independent t-test. Statistical significance was set at P ≤ 0.05 for all tests. Results are reported as mean ± SEM.
Chronic restraint stress reduced body weights
First, we examined the effects of 3 wk of chronic restraint stress on body weight. Data were presented as percentage change compared with baseline (Fig. 2). As expected, we found there was a significant time main effect (F31, 1581 = 343, P < 0.001), significant time–treatment interaction (F93, 1581 = 25, P < 0.001), and a significant treatment main effect (F3, 51 = 20, P < 0.001), demonstrating that chronic restraint stress significantly reduced body weight relative to nonstressed controls, but no significant differences existed among the three stressed groups (Fig. 2).
Chronic restraint stress-induced adrenal hypertrophy, but does not affect spleen weight
We also found a significant treatment effect (F3, 51 = 6.45, P = 0.001) for adrenal (Fig. 3) but not spleen (F3, 51 = 0.75, P = 0.526; data not shown), weights indicating that chronic restraint stress resulted in significant adrenal hypertrophy compared with nonstress controls, but no differences were observed among the three stressed groups.
Effects of exercise on anti-OVA IgM responses to vaccination in chronically stressed mice
Additionally, we investigated whether acute eccentrically biased downhill running and voluntary wheel exercise training could attenuate stress-induced reductions in antibody responses to vaccination. We examined both anti-OVA IgM and anti-OVA IgG responses to vaccination. When we examined the anti-OVA IgM responses, we found that there was a significant time main effect (F2, 102 = 6.26, P = 0.003) as expected, demonstrating plasma anti-OVA IgM increased significantly at 1, 2, and 4 wk relative to preimmunization levels. We did not find significant time–treatment (F6, 102 = 1.36, P = 0.240), or a treatment main effect (F3, 51 = 1.46, P = 0.237) (Fig. 4). Neither ECC nor voluntary wheel exercise training affected anti-OVA IgM responses.
Effects of exercise on Anti-OVA IgG responses to vaccination in chronically stressed mice
When we examined the anti-OVA IgG responses, we found a significant time main effect (F2, 102 = 164, P < 0.001), demonstrating plasma anti-OVA IgG increased significantly at 1, 2, and 4 wk relative to preimmunization levels. We did not find significant time–treatment (F6, 102 = 0.70, P = 0.648), but there was a significant treatment main effect (F1, 51 = 413, P < 0.001) (Fig. 5). Post hoc Bonferroni tests revealed that ECC significantly attenuated stress-induced anti-OVA IgG responses at 4 wk postvaccination. Voluntary wheel exercise training significantly attenuated stress-induced anti-OVA IgG responses at both 2 and 4 wk postvaccination. In summary, we report that both ECC and voluntary wheel exercise attenuated chronic restraint stress-induced suppressions in anti-OVA IgG, but not anti-OVA IgM responses to vaccination.
Effects of exercise on cell-mediated responses to vaccination on chronically stressed mice
In addition, we examined whether acute eccentrically biased downhill running and voluntary wheel exercise training could attenuate stress-induced reductions in cell-mediated immune response to vaccination. We found there was significant time main effect (F6, 306 = 9.72, P < 0.001), demonstrating that ear swelling increased significantly in all groups (Fig. 6). However we did not find a significant time–treatment interaction (F18, 186 = 1.00, P = 0.458) nor treatment main effect (F3, 51 = 1.96, P = 0.131). Neither ECC nor voluntary wheel exercise training affected DTH responses.
This study examined the effects of acute eccentrically biased downhill running and voluntary wheel exercise training on immune responses to vaccination in chronically stressed mice. We conclude that chronic restraint stress reduced body weight and caused adrenal hypertrophy. Both ECC and voluntary wheel exercise training attenuated chronic restraint stress-induced suppressions in anti-OVA IgG, but not anti-OVA IgM nor cell-mediated immune responses to vaccination.
There have been several studies exploring the effects of acute moderate exercise on vaccination in humans. Edwards and colleagues (4–6) recently conducted a series of experiments using eccentrically biased exercise to examine the effects on vaccination responses. For all three studies, the participants in exercise groups performed the eccentric portions of the bicep curl and lateral raise exercise, contracting the biceps brachii and deltoid muscles of the nondominant arm, respectively. Influenza vaccine was administered to the deltoid muscle, where the muscle damage and inflammatory response occurred. In the first study, moderate exercised women had an increased antibody response, whereas men showed enhanced cell-mediated responses compared to the control group (5). The second study showed that all exercise groups, regardless of intensity (light, moderate, and heavy), exhibited significantly higher antibody responses compared with the control group when vaccinated immediately after exercise (6). In both of the studies above, elevated influenza antibodies were observed between 4 and 6 wk after inoculation, which is in line with our current study findings. IgG antibody is produced during the primary immune response and usually peaks about 4 wk. Although unclear, it might be one of the reasons exercise only mitigated the stress-induced decline in anti-OVA IgG at a later time points (2 and 4 wk).
Exercise training has been shown to promote antibody responses to vaccine in elderly by our group and others. We demonstrated that cardiovascular exercise training extended influenza vaccine seroprotection in sedentary older adults (12). Participants performing 10 months of moderate (60%–70% maximal oxygen uptake) cardiovascular exercise were compared with subjects doing flexibility and balance training. Cardiovascular exercise elicited a significant increase in the seroprotective response 24 wk postvaccination compared with the flexibility controls. Two additional studies conducted similar moderate exercise training interventions in elderly and found that compared with sedentary group, exercise training enhanced antibody responses to influenza and keyhole-limpet hemocyanin (KLH) immunization, respectively (11,18). These studies above demonstrate that chronic exercise training can improve antibody responses to vaccination older adults. In contrast, Long et al. (13) studied a lifestyle physical activity intervention and the antibody response to pneumococcal vaccination in middle-age women and found that the intervention did not increase the antibody response. One of the explanations for the different findings may be the age differences of participants. Middle-age adults do not exhibit age-associated immunosenescence, thus, physical activity cannot further improve already-robust immune responses. In previous studies, antibody elevation occur in people 65 yr and older. Based on this evidence, it is important to perform mechanistic experiments in age mice or use less than full-dose vaccination in young mice, where there is weaker control response, to determine whether exercise can improve suboptimal immune responses to vaccination.
Our findings suggest that exercise was associated with improved IgG, but not IgM antibody production in chronically stressed mice. One of the earliest studies in rodents models demonstrated 8 wk of moderate training enhanced Th-1 associated cytokines, but not IgM antibody production in age mice in responses to herpes simplex virus type 1 (HSV-1) (19). However, they did not assess anti-HSV IgG levels. Another study failed to show an increase of anti-KLH IgG in responses to 10 wk of treadmill training in age rats (20). Although unclear, one potential explanation for the difference may be a difference in exercise models. In our study, we used voluntary wheel running, whereas this investigation used treadmill training. The differences between mice and rats may also contribute to the results. Liu et al. reported a positive effect of voluntary wheel running exercise training on antibody responses to Salmonella typhi infection in mice (21). However, they assessed the secondary immune response, whereas our current study measured primary antibody responses. IgM antibody provides immediate response when an antigen occurs, whereas IgG responds later with the permanent eradication of the antigen and is longer lasting. IgG is also involved in secondary immune response developing. Therefore, enhancing antigen-specific IgG responses may be more important.
Delayed-type hypersensitivity skin testing has long been used in clinical settings to assess inflammatory reaction and global cell-mediated immunity in vivo. This current study did not show beneficial effect of exercise on DTH responses, which is consistent with our laboratory previous findings in the human study. We reported no differences in DTH responses to fungal antigens between high physically fit and low-fit elderly (22). Along with these lines, high-intensity resistance training also has not been shown to alter DTH responses in older adults (23). However, Smith et al. (24) found physically active older men exhibited higher DTH responses to KLH compared with the sedentary older group. To our knowledge, there is a lack of studies exploring the effect of exercise on DTH responses in an animal model of immunosenescence. Reasons of different findings may include variabilities of self-reporting data due to the nature of cross-sectional studies and different exercise modes which are aerobic versus resistance training. Small samples sizes is also a limitation using DTH as a functional measure of cell mediated immunity as large variability typically observed.
Few studies have investigated the effects of exercise on immune responses to vaccination in stressful situations, more have focused on effects of stress and disease-related immune regulation. Luo et al. (25) examined the moderating impact of moderate exercise on chronic stress-induced intestinal barrier dysfunction. Mice were subjected to repeated restraint stress for 6 h·d−1 for 7 d (or no stress), receiving 30 min swimming before each stress session (or sedentary). Swimming before stress attenuated bacterial translocation, maintained intestinal permeability and significantly increased gene expression of four antimicrobial peptides. In conclusion, they found that brief moderate exercise attenuated chronic stress-induced intestinal barrier dysfunction and enhanced innate mucosal defenses. Some human studies also reported beneficial effects of physical activity or structured exercise on disease-related immune regulation (26,27). Bote et al. (26) showed an 8-month aquatic exercise training resulted in an anti-inflammatory effect, including decreased systemic levels of IL-8 and tempered neutrophil activation (chemotaxis) in fibromyalgia syndrome patients.
Early evidence has suggested that moderate exercise training have the potential to alleviate stress-induced immunosuppression. Brown and Siegel (28) investigated the ability of physical exercise to buffer stress-induced disease incidence in adolescence. The findings suggest that girls who were moderately physically active were more protected against the immunologically deleterious consequences of stress compared to the sedentary girls under high stress. In an animal study, Moraska and Fleshner (29) reported that 4 wk of voluntary wheel running reduced tail shock stress-induced behavioral depression and prevented stress-induced suppression of anti-KLH IgM and IgG2a antibodies in rats.
There are some potential limitations to this study. Use of males only is consistent with previous rodent studies, which investigate the effects of exercise or stress in general, on immune responses to vaccination (2,30,31), most likely to minimize the confounding factor of female reproductive cycle on study outcomes. However, human studies have reported different antibody or cell-mediated responses to vaccination in men and women (5). Pascoe et al. (32) proposed that exercise beneficial effect only observed in men or women was because of their differences in the control responses. Beneficial effects were only observed in the weaker control responses group. Future experiments will need to further understand the mechanisms underlying the beneficial effect of exercise on immune response to vaccination in chronically restraint stressed mice and test whether exercise-induced improvements in vaccination responses leads to protective effects related to infectious diseases.
The authors state that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The authors report no conflict of interest. The results of the present study do not constitute endorsement by ACSM.
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