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J Appl Physiol 104: 1690-1696, 2008. First published April 10, 2008; doi:10.1152/japplphysiol.01044.2007
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Exercise training enhances in vivo tuberculosis purified protein derivative response in the elderly

Mitsuharu Okutsu,1 Yuko Yoshida,2 Xiumin Zhang,3 Akira Tamagawa,3 Takayoshi Ohkubo,4 Ichiro Tsuji,5 and Ryoichi Nagatomi3

1Consolidated Research Institute for Advanced Science and Medical Care, Waseda University, Tokyo, 2Research Team for Promoting Independence of the Elderly, Tokyo Metropolitan Institute of Gerontology, Tokyo, 3Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, 4Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, and 5Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

Submitted 30 September 2007 ; accepted in final form 25 March 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
We investigated the effect of 25 wk of exercise training on in vivo immune measures that depend on T helper 1 (Th1) and T helper 2 (Th2) immune responses in the elderly as a substudy of a randomized controlled trial to investigate health benefits of regular exercise training for the elderly. Sixty-five healthy elderly volunteers were randomly assigned to either an exercise training group (n = 32) or a sedentary control group (n = 33). The area of skin reaction to purified protein derivative (PPD) of tuberculin that depends on Th1 activation and the concentrations of serum IgG subclasses and IgE were evaluated before and after 25-wk intervention. All participants completed 25 wk of training. Thirty-one participants of the exercise group and all control group underwent immunological analyses, but only 30 from the exercise group and 21 from the control group had the PPD skin reaction assessment. Repeated-measures ANOVA revealed a significant interaction between time and exercise intervention, which appeared as an enhanced skin reaction to tuberculin PPD (P < 0.05) and a reduced serum IgG4 concentration, the production of which depends on Th2-dependent class switching (P < 0.05), in the exercise group after 25 wk. No immune variables changed in the control group. These result supports the hypothesis that exercise training favors in vivo Th1 immune response in elderly persons.

delayed-type hypersensitivity; T helper 1 cells; immunoglobulin G4

T-CELL FUNCTIONS SUCH AS CYTOKINE production and cytotoxic effector functions in antigen recognition are essential for human adaptive immune defense and are subject to immune senescence. Mitogen-induced IL-2 and IFN-{gamma} synthesis and T-cell proliferation decline with age (7). Elderly people generally exhibit significantly lower CD8+ cytotoxic T-cell responses to mitogenic stimuli compared with younger people (3).

T helper cells with regulatory roles are subclassified into several distinct populations by their cytokine production patterns. T helper 1 (Th1) and T helper 2 (Th2) cells are important because they support two major aspects of the adaptive immune responses. Th1 cytokines, such as IL-2 and IFN-{gamma}, support cell-mediated inflammatory reactions by activating cytotoxic and inflammatory functions, and Th2 cytokines, such as IL-4, IL-5, IL-6, IL-10, and IL-13, support humoral immune responses (19, 20). Th1 and Th2 cytokines are mutually inhibitory for the differentiation and effector functions of the reciprocal phenotype (8, 20). IFN-{gamma} selectively inhibits proliferation of Th2 cells, and IL-4 and IL-10 inhibit cytokine synthesis by Th1 cells (20). This cross-regulation strongly biases the Th1 vs. Th2 responses during many infections in mice and humans (20).

Th1 clones are shown to induce delayed-type hypersensitivity (DTH) skin reactions (4), and IFN-{gamma} is commonly expressed at sites of DTH reactions (10), whereas IgG4 and IgE production are known to be dependent on Th2-supported class switching. IgE production in allergic responses is strongly associated with Th2 activation (17, 23, 25).

A number of studies show that physical exercise affects Th1 and Th2 immune responses and the balance between these responses. Strenuous exercise decreases the percentage of circulating Th1 lymphocytes (28). Acute exhaustive exercise or short-term intense training significantly reduces the percentage and number of circulating Th1 cells but not of Th2 cells in endurance-trained cyclists (16). If the reduction in Th1 cytokine-releasing cells is associated with an attenuation in the Th1 immune response, such a reduction in frail elderly people may increase the risk of infection. There is, however, little evidence that exercise in apparently healthy elderly people increases their risk of infection. Rather, it is commonly believed that regular moderate exercise is beneficial. Our hypothesis is that the exercise regimens commonly employed for the elderly to maintain their physical functions and cardiovascular fitness may improve the T helper immune responses and perhaps potentiate Th1 immune response.

The aim of this study was to determine whether health-oriented exercise training employed to improve cardiovascular fitness would also maintain or potentiate Th1 immune responses in healthy elderly people. We tested our hypothesis in a substudy of a randomized controlled trial of a 25-wk exercise program in elderly people (Sendai Silver Center Trial), in which improvements in cardiovascular fitness and increased daily energy expenditure occurred in the ET group have been demonstrated (11, 29). Because Nakayama et al. (21) reported that nonresponders to the tuberculin PPD skin test, who had fewer circulating CD4+ T lymphocytes and Th1 cells than responders among immobile elderly subjects, had a higher risk of developing pneumonia, the tuberculin PPD skin reaction was employed as a clinically relevant measure associated with Th1 response. Because the tuberculin PPD response is antigen specific and may not reflect a general trend of Th1 and Th2 immune responses, serum IgG subclass concentration was measured, because Th1 immunity is known to be connected to the IgG1 and IgG3 subclasses (2, 22, 27, 30) and Th2 immunity to the IgG4 isotype and IgE (17). Therefore, the skin DTH reaction to tuberculin PPD, which is associated with IFN-{gamma} producing Th1 activity, and serum level of IgG4, which is produced depending on Th2 activation, were evaluated before and after the 25-wk supervised exercise program.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Design.   This is a subsidiary study of the Sendai Silver Center Trial. Sendai Silver Center Trial was a randomized controlled trial in which health benefits of regular exercise training for the elderly was investigated (29). The protocol of the present study was approved by the Exercise Board of the Sendai Health and Welfare Foundation.

Study participants.   Full details of selection criteria for the participants are in the previous report (29). We recruited through municipal advertisements independently living men and women aged 60 yr or older who resided in Sendai City. A total of 209 potential participants applied and attended the screening session. Of these, 121 were excluded for one or more of the following reasons: 1) moderate to severe motor impairment or neurological deficits; 2) a history of coronary heart disease within 6 mo of the study; 3) patients with hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg); 4) joint pain or arthritis limiting the full range of motion at shoulder, elbow, hip, or knee joints; 5) mental or other conditions that could interfere with participation; 6) other chronic disease that could interfere with participation; 7) history of fracture of a lower extremity or injurious falls within 6 mo of the study; or 8) use of antihypertensive agents, antiarrhythmic agents, nitroglycerides, digitalis, or vitamin supplements. Of the 88 remaining applicants, 78 attended the baseline measurement examination. A further 12 were excluded because of abnormal exercise electrocardiograms. The remaining 65 were grouped for age and sex and randomly allocated into either the exercise training group (ET, n = 32) or control group (C, n = 33) by epidemiologists who were masked from the measurement results (Fig. 1). All participants gave written informed consent. Baseline age, female sex, height, weight, and maximum oxygen consumption (VO2 max) were not significantly different between ET and C groups (Table 1).


Figure 1
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  		Fig. 1. Flow chart showing numbers, training interventions, and outcome measures of the randomized exercise and control groups. *Exclusion criteria: 1) moderate to severe motor impairment or neurological deficits; 2) a history of coronary heart disease within 6 mo of the study; 3) patients with hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg); 4) joint pain or arthritis limiting the full range of motion at shoulder, elbow, hip, or knee joints; 5) mental or other conditions that could interfere with participation; 6) other chronic disease that could interfere with participation; 7) history of fracture of a lower extremity or injurious falls within 6 mo of the study; or 8) use of antihypertensive agents, antiarrhythmic agents, nitroglycerides, digitalis, or vitamin supplements. PPD, purified protein derivative.

 

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  		Table 1. Baseline characteristics of the subjects

 
Two participants from the ET group and 12 participants from the C group did not agree to undergo tuberculin PPD examination for nonmedical, personal reasons. There were no statistical differences in all the baseline parameters between subjects who refused tuberculin PPD and subjects who agreed tuberculin PPD, as well as between the C group and ET group subjects who agreed to undergo tuberculin PPD responses.

Because steroidal and nonsteroidal anti-inflammatory medication or aspirin may largely affect the result of this study, those who took such medication throughout the study were to be excluded from the PPD examination. Medication status was checked every week on the occasion of exercise participation and monthly C group classes throughout the study.

ET group.   We gave three 2-h classes per week for 25 wk. The participants in the ET group were asked to attend the classes at the Center at least twice a week. Each class started with a 30 min warm-up session, including static stretching of extremities and trunk muscles followed by a 10-min low-intensity stepping exercise. The main session consisted of an endurance exercise session using a bicycle ergometer and a resistance exercise session using rubber films.

Endurance exercise session   Participants cycled at 50–60 revolution/min on a bicycle ergometer at an individually prescribed intensity for 10–25 min. (Table 2). The intensity of exercise was determined according to the guidelines for exercise prescription of American College of Sports Medicine. The intensity of exercise was calculated as a percentage of heart rate reserve, based on the participant's predicted age-adjusted maximum heart rate (220 – age). Heart rate was monitored throughout the endurance training to check whether exercise of the prescribed intensity was accomplished. The initial intensity of exercise was set at 5–20 W. The subject increased the exercise intensity under the supervision of exercise trainers to reach the target heart rate at fifth minute of exercise. When the heart rate exceeded the target by 5% heart rate reserve for more than 2 min, exercise intensity was reduced until subjects reached their target heart rate.


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  		Table 2. Exercise prescription for endurance training

 
Resistance exercise session.   Five types of exercise using rubber film manufactured for resistance exercise (Thera-Band Resistive Exerciser, Hygienic, Akron, OH) were performed in a five-stage incremental program under the supervision of an expert exercise trainer. Side raise for supraspinatus and deltoid muscles, elbow flexion for biceps muscle, knee extension for quadriceps muscle, hip abduction, and hip adduction were each repeated 20 times per session. Rubber films of various strengths were coded by colors and adjusted to appropriate lengths for each participant and each exercise. The strengths of the rubber films were selected so that each set of 20 repetitions exhausted the loaded muscle (20 repetitions maximum). In the last class of each stage, each participant was asked to repeat the exercise until exhaustion. If the participant could repeat it more than 25 times, we increased the strength of the rubber film for the next stage. The resistance training session was periodized to avoid chronic fatigue of the participants as well as the endurance training sessions. To minimize excessive fatigue, the subjects performed only three types of resistive exercise in the initial 5 wk followed by 5 wk of secondary acclimatization stage in which exercise intensity or the strength of rubber films was increased within a low range so that the participants could perform resistive training with medium level of effort without exhaustion or muscle soreness. Four-week building-up phases started from 11th wk. After 11th wk, at every 4 or 5 wk exercise frequency or rubber film strength was reduced to allow recovery from muscle soreness or fatigue (15th, 19th, and 22th wk).

Safety considerations.   To ensure safety, a research nurse and a physician checked the health status and vital signs of each participant before and after each class, and they attended the classes (29).

Control group.   We provided two 2-h classes a month to avoid dropouts. The participants were asked to attend classes at least once a month. The classes consisted of a 1-h lecture, the topic of which was not related to physical exercise, and 1 h of seated recreational activity. Otherwise, they were asked to continue their daily activities.

VO2 max measurement.   VO2 max was estimated by stepwise incremental exercise on a bicycle ergometer. Participants were told to pedal at a constant rate of 60 ± 10 rpm. The initial workload was set at 10 W. The workload was increased thereafter 5–30 W stepwise each 2 min until the participant reached the age-adjusted target heart rate (85% age-adjusted maximal heart rate). Oxygen uptake every minute during the incremental exercise session was recorded using an expired-gas analyzer (AeroMonitor 280, Minato Medical Science, Osaka, Japan). VO2 max was estimated by linearly extrapolating the oxygen uptake as a function of heart rate up to age-adjusted maximal heart rate.

Blood sampling.   Blood samples were obtained before and after the training period and analyzed. Blood sampling was performed at least 1 wk after and no later than 2 wk after the last exercise bout. No participant had a medical history of allergy. Participants refrained from any moderate or heavy exercise for at least 12 h before blood sampling. No food or drink other than water was allowed for 10 h before blood sampling. Blood samples were drawn from antecubital veins in the morning between 8:00 and 10:00 AM, with sterile syringes containing 100 IU of heparin (Novo Nordisk, Copenhagen, Denmark) per 10 ml of blood for either mononuclear cell preparation or plasma separation, and with sterile syringes without anticoagulants for serum separation.

Total and differential white blood cell count.   Total white blood cell (WBC) count was measured by using a Sysmex microcell counter SE-9000 (Sysmex, Kobe, Japan). The proportions of lymphocyte, monocyte, neutrophil, eosinophil, and basophil in peripheral blood samples were evaluated by the standard morphological technique using May-Giemsa-stained samples. The absolute number of each cell type was calculated from the total WBC count and the percentage of each type.

Lymphocyte subsets staining.   Heparinized peripheral blood was stained with biotin-labeled anti-CD3, FITC-labeled anti-CD4 monoclonal antibody (mAb), and phycoerythrin-labeled anti-CD8 mAb. Isotype controls were used in this assay to account for the background binding of Ig. All the mAbs were purchased from BD Biosciences (San Jose, CA). After 30 min incubation with monoclonal antibodies at 4°C, cells were washed twice in ice-cold PBS, and then incubated with streptavidin-RED670 (Gibco BRL, Grand Island, NY) to visualize biotinylated antibody. After a 20 min incubation with streptavidin-RED670 at 4°C, heparinized peripheral blood was hemolyzed with FACS lysing solution (BD Biosciences). Cells were then washed twice in ice-cold PBS and were analyzed by three-color flow cytometry (BD Biosciences).

Serum concentration of IgE and IgG subclasses.   Serum concentration of IgE and IgG subclasses was measured by fluoroenzyme immunoassay (Pharmacia and Upjohn, Uppsala, Sweden) or ELISA (Zymed Laboratories, San Francisco, CA).

Skin reaction to tuberculin PPD.   A 0.1-ml saline solution containing 0.05 mg of tuberculin PPD (Japan BCG Laboratory, Tokyo, Japan) was injected intradermally at the anterior aspect of the forearm, avoiding superficial veins, by an experienced medical doctor using the standard clinical procedure. After the injection, participants were told not to undertake vigorous exercise until the skin reaction was evaluated. Skin reaction was evaluated 48 h after the injection by measuring the longitudinal and horizontal dimensions of both the palpable induration and the skin flush with a pair of vernier calipers by an experienced medical doctor who was blinded to the group assignments of the participants. The areas of both the skin indurations and the skin flush were calculated as the area of an oval. Skin reaction was also photographed together with a scale for future review. The same lot of PPD preparation was used throughout the study. Participants who exhibited hyperreaction with extended swelling and skin ulceration underwent clinical assessment for tuberculosis infection, including breast X-ray examination and examination of C-reactive protein. Hyperreactive participants were excluded from posttraining PPD examination. PPD skin test was performed at least 1 wk after and no later than 2 wk after the last exercise bout.

Statistical analysis.   Values shown in the tables are presented as means ± SE. ANOVA for two (group) x two (time) repeated measures was used to determine the effect of treatment during the 25-wk period between each group. All post hoc comparisons were performed using Fisher's positively least significant difference test. A {chi}2 test was performed to test the differences in the proportion of PPD nonresponders and responders between groups at baseline. All statistical analyses were performed with StatView software (SAS Institute, Cary, NC). P < 0.05 was considered to be statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Throughout the 25 wk of intervention, there were no drop-outs from either group. The mean attendance rate for each class was 78.2% in the ET group and 84.5% in the C group. In the ET group, 28 subjects (82%) attended at least twice in a week throughout the 6-mo program. In the C group, 31 subjects (94%) attended their classes at least once a month throughout the 6-mo program. One woman was unable to attend the postintervention measurement session for a nonmedical personal reason. Analyses were therefore based on 31 participants from the ET group and 33 C group participants (Fig. 1).

Physical characteristics of participants.   Estimated VO2 max increased from 25.6 ± 5.3 to 27.1 ± 5.1 ml–1·kg·–1min after 25 wk of exercise training (F value = 4.44, P < 0.05). There was no significant difference in estimated VO2 max before and after 25 wk in the C group. There was no significant difference in the other parameters before and after exercise training in either groups.

Cell count.   Blood samples from 62 out of 64 participants (ET: men/women = 14/15; C: men/women = 15/18) were analyzed; three blood samples were excluded from the analysis because of apparent hemolysis and possible clotting. As shown in Table 3, the mean values of circulating cell counts at baseline were not significantly different between the ET and C groups. Within the ET group, counts of WBC (before: 5,009.4 ± 234.0 and after: 5,458.7 ± 273.7), and neutrophils (before: 2,545.6 ± 166.9, and after: 3,216.7 ± 185.8) were increased after 25 wk of exercise. Blood lymphocyte count (before: 2,064.6 ± 130.0 and after: 1,826.3 ± 112.4) was decreased after 25 wk of exercise, Within the C group, counts of WBC (before: 4,670.6 ± 146.4 and after: 5,067.6 ± 156.7) and neutrophils (before: 2,065.7 ± 104.0 and after: 2,963.3 ± 134.1) were increased after the 25-wk exercise period. Blood lymphocyte count (before: 2,204.9 ± 110.6 and after: 1,784.9 ± 102.8) was decreased after 25 wk of exercise, Between-group analysis showed that circulating cell counts were not significantly different before and after exercise training.


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  		Table 3. Changes in the number of circulating leukocytes

 
Circulating T-lymphocyte subsets.   As shown in Table 4, the mean values of T-cell subsets at baseline were not significantly different between the ET and C groups. Within the ET group, the percentage of CD4+ CD8– (53.6 ± 2.0 to 51.5 ± 2.2) was decreased, and CD4– CD8+ (35.2 ± 2.0 to 38.0 ± 2.3) was increased, after the 25-wk exercise period. Between-group analysis showed that circulating T-cell subsets were not significantly different before and after exercise training.


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  		Table 4. Changes in the percentage of CD4 and CD8 T-lymphocyte subsets

 
Skin reaction of tuberculin PPD.   Physical characteristics of the ET and C group participants who agreed to undergo PPD skin testing were not significantly different at baseline. Skin induration of 5 mm or more in diameter was considered to be a positive reaction. Four participants (2 from each of the ET and C groups) who developed a strong skin reaction accompanied by necrotizing skin inflammation did not participate in the posttraining PPD test. Seven and four nonresponders in ET and C groups, respectively, demonstrated neither skin reaction nor induration of >5 mm in diameter. There were no statistical differences in the proportion of positive responders between the ET and C groups at baseline ({chi}2 test) as well as at the posttraining assessment. Therefore, the analysis for the effect of exercise intervention involved 20 participants (men/women = 12/8) from the ET group and 15 participants (men/women = 8/7) from the C group, although there were no significant differences in major characteristics at baseline between these two groups.

After the training intervention, we found DTH response to tuberculin PPD was enhanced in the ET group but not in the C group (Fig. 2). There was a significant group x time interaction (P < 0.05) in repeated-measures ANOVA. In terms of skin responsiveness, both responders and nonresponders remained responders and nonresponders after the intervention. Their systemic inflammatory markers such as C-reactive proteins or WBC counts were within normal limits at the time of examination, and there were no signs of fresh or reactivating lung tuberculosis (data not shown).


Figure 2
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  		Fig. 2. Change in skin reactions to tuberculin PPD before and after the training period. Error bars represent SE of the mean. Twenty-nine participants from exercise training (ET) group and 21 participants from the control (C) group agreed to undergo tuberculin PPD examination. Among them, 4 participants (2 from each of the ET and C groups) who exhibited necrotizing skin inflammation did not undergo posttraining examination. Seven participants in the ET group and 4 participants in the C group were nonresponders to PPD, and they remained nonresponsive in the postintervention examination. PPD- delayed-type hypersensitivity responses of the participants excluding hyperresponsive and nonresponsive participants were analyzed (ET group: n = 20, men/women = 12/8; C group: n = 15, men/women = 8/7). The DTH response in the ET group after training was significantly higher than before training. However, there was no significant difference in DTH response before and after training in the C group. There was a significant group x time interaction in repeated-measures ANOVA analysis (*P < 0.05).

 
Concentration of serum IgE and IgG subclasses.   The mean values of serum IgE and IgG subclass concentrations at baseline were not significantly different between the ET and C groups. There were no significant differences in the serum concentration of IgE and IgG2 subclasses before and after training in either group (Table 5). Levels of IgG1 and IgG3 were decreased significantly after training, but there was no significant group differences. The level of serum IgG4 was decreased significantly in the ET group after training, whereas it was unchanged in the C group. The group difference in the change in serum IgG4 was statistically significant (P < 0.05).


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  		Table 5. Changes in serum IgE and IgG subclass concentration

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The aim of this substudy of a randomized controlled trial for investigation of health benefits of exercise training on elderly participants was to examine whether health-oriented exercise training normally used to improve cardiovascular fitness would affect tuberculin PPD responses in healthy elderly people. Although not all the subjects underwent immunological assessment, enhanced DTH reaction of tuberculin PPD and reduced serum IgG4 concentrations were found among the exercise participants posttraining, which was not observed among the C group subjects, who did not attend exercise sessions.

Whereas tuberculin PPD skin reaction is specific antigen dependent, serum IgG4 may depend on wide spectrum of unknown antigens. Nevertheless, immunodeficient patients with mutant GATA-3, a well-established transcription factor crucial for Th2 differentiation (31) demonstrate markedly decreased serum IgG4 concentration as well as scarcely detected Th2 cytokine-producing cells in the bloodstream (25). Serum IgG4 level may therefore be considered as a reflection of Th2 immunity. Simultaneous enhancement in the skin reaction to tuberculin PPD and the reduction of serum IgG4 after 6 mo training in this study thus seems to be in accordance with the reciprocal regulation of Th1 and Th2 immune responses. We, therefore, suggest chronic exercise training in healthy elderly people appears to favor in vivo Th1 immune responses.

In this study, serum IgG4 was decreased after training and no change was observed in the C group. However, the levels of IgG1 and IgG3, both known to be Th1 dependent, significantly decreased after 25-wk training period both in the ET group and the C group. Because postintervention blood sampling was performed later than 1 wk after the last exercise session, we assume that the acute effect of exercise was negligible. Baseline measurement was in March, and postintervention measurement was in October. We assume this common decrease in IgG1 and IgG3 may be because of the seasonal variation, because the decrease was common to both groups accompanied by increases in the neutrophil count and decreases in the lymphocyte counts. Seasonal effect on Th1 and Th2 immune responses will be an interesting focus of investigation in scope of allergic diseases due to pollen and other plant components.

Anti-influenza IgG and IgM levels in response to vaccination were reported to be greater in the active population, who engaged in more than 20 min of vigorous exercise three or more times per week, compared with the moderately active population, who engaged in regular exercise with less intensity, frequency, or duration, or sedentary populations (15). Because the initial IgG and IgM responses to vaccines or viral infection are considered to be Th1 dependent (24), greater anti-Influenza IgG and IgM response in the active population may be associated with enhanced Th1 capacity as observed in this study.

Two cross-sectional studies have examined the relationships between physical activity or fitness and DTH response. Smith et al. (26) found that the physically active older group had significantly higher anti-keyhole limpet hemocyanin IgM, IgG, IgG1, and DTH responses, but not IgG2, compared with the sedentary older group. Keylock et al. (14) found no differences between fitness groups in DTH skin test responses but did find differences to two fungal antigens, trichophyton and candida (14). Although these studies had controls for differences in health, psychosocial status, and nutrition, cross-sectional studies by their nature could be limited.

Another study examined the effect of exercise and food intervention on DTH responses in frail elderly people. That study reported a significant decline in DTH responsiveness in nonexercising subjects compared with unchanged responsiveness in exercising subjects (5). They did not find the enhancement in DTH response that we did in our exercising subjects. One of the reasons that they could not demonstrate improvement may be that their subjects were on average more than 10 yr older than our subjects. However, considering the age-related decline in immune response, both sets of results suggest that exercise training may prevent or slow the aging process.

The first phase of the DTH reaction involves uptake, processing, and presentation of the antigen by local antigen-presenting cells. Dendritic cells (DC) are likely to play a key role in immunity to Mycobacterium tuberculosis. DC exhibit the unique ability to ingest pathogens at the site of infection and to migrate to secondary lymphoid organs, such as lymph nodes, where they present pathogen-derived antigens to naive T lymphocytes (1). Priming and activation of mycobacterial antigen-specific T lymphocytes are essential for protection against tuberculosis (9, 13). Acute exercise or surgical stress raises circulating DC counts (12). We could not assess an in vivo DC function or distribution for ethical reasons, and this is one of the limitations of this study.

Nakayama et al. (21) showed that elderly nonresponders to tuberculin PPD had a higher probability of developing pneumonia when compared with the responders (21). Our nonresponders to PPD remained nonresponders even after exercise training in this study. Therefore, we cannot simply conclude that enhanced DTH response in this study favors resistance to pneumonia. Although PPD reactivity is strongly associated with clinical outcome, the clinical significance of the enhanced DTH response remains to be determined.

There are two limitations in this study. First, we could not recruit all the study participants of Sendai Silver Center Trial into PPD measurement, especially in the C group. One of the reasons for the refusal may be because of the negative attitude towards tuberculosis related testing of the elderly people in Japan. In 1957, when the majority of the study participants were in their adolescence and young adults, the prevalence of registered tuberculosis patients for the age group of 20 in Japan was 409.9/100,000 (18). Nevertheless, smaller number of control participants could be a potential bias in the interpretation of our result. But, because we found no statistical difference in the distribution of PPD nonresponders, nor the following parameters that may potentially affect the exercise responses; VO2 max, age, sex, body weight, and height, at baseline we considered our result still significant as a controlled study. Second, psychological stress modulates immunity response in the elderly. Higher levels of anger, fatigue, and overall mood disturbance are related to lower Th1 cytokine responses to live virus, whereas vigor and optimism are related to greater Th1 cytokine response to live virus (6). Because we could not collect information of psychosocial factors, psychological study is necessary to further understand the regulation of tuberculin PPD responses.

In conclusion, we demonstrated that a 25-wk program of moderate exercise training for the healthy elderly significantly enhanced tuberculin PPD skin DTH reaction, which depends on Th1 activation. PPD skin reaction was significantly enhanced only in the ET group, but exercise did not render nonresponders to PPD to responders. These data confirm and extend the existing literature regarding the influence of exercise training on immune responses and support the need for further cross-sectional studies of cell-mediated immune responses in older adults.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported by research grants from Ministry of Education and Culture (09557034) and Ministry of Health and Welfare (Research on Health Services: H10-025), Japan.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
This study was conducted by the Sendai Silver Center Trial study group (29).


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. Nagatomi, Medicine and Science in Sports and Exercise, Tohoku Univ. Graduate School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai 980-8575, Japan (e-mail: nagatomi{at}mail.tains.tohoku.ac.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 392: 245–252, 1998.[CrossRef][Medline]
  2. Bonifacio E, Scirpoli M, Kredel K, Fuchtenbusch M, Ziegler AG. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J Immunol 163: 525–532, 1999.[Abstract/Free Full Text]
  3. Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schachter F. CD28 expression in T cell aging and human longevity. Exp Gerontol 33: 267–282, 1998.[CrossRef][Web of Science][Medline]
  4. Cher DJ, Mosmann TR. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol 138: 3688–3694, 1987.[Abstract]
  5. Chin APMJ, de Jong N, Pallast EG, Kloek GC, Schouten EG, Kok FJ. Immunity in frail elderly: a randomized controlled trial of exercise and enriched foods. Med Sci Sports Exerc 32: 2005–2011, 2000.[CrossRef][Web of Science][Medline]
  6. Costanzo ES, Lutgendorf SK, Kohut ML, Nisly N, Rozeboom K, Spooner S, Benda J, McElhaney JE. Mood and cytokine response to influenza virus in older adults. J Gerontol A Biol Sci Med Sci 59: 1328–1333, 2004.[Abstract/Free Full Text]
  7. Ernst DN, Weigle O, Hobbs MV. Aging and lymphokine gene expression by T cell subsets. Nutr Rev 53: S18–S25; discussion S25–S26, 1995.[Web of Science][Medline]
  8. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170: 2081–2095, 1989.[Abstract/Free Full Text]
  9. Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol 19: 93–129, 2001.[CrossRef][Web of Science][Medline]
  10. Fong TA, Mosmann TR. The role of IFN-gamma in delayed-type hypersensitivity mediated by Th1 clones. J Immunol 143: 2887–2893, 1989.[Abstract]
  11. Fujita K, Nagatomi R, Hozawa A, Ohkubo T, Sato K, Anzai Y, Sauvaget C, Watanabe Y, Tamagawa A, Tsuji I. Effects of exercise training on physical activity in older people: a randomized controlled trial. J Epidemiol 13: 120–126, 2003.[Web of Science][Medline]
  12. Ho CS, Lopez JA, Vuckovic S, Pyke CM, Hockey RL, Hart DN. Surgical and physical stress increases circulating blood dendritic cell counts independently of monocyte counts. Blood 98: 140–145, 2001.[Abstract/Free Full Text]
  13. Kaufmann SH. How can immunology contribute to the control of tuberculosis? Nat Rev Immunol 1: 20–30, 2001.[CrossRef][Medline]
  14. Keylock KT, Lowder T, Leifheit KA, Cook M, Mariani RA, Ross K, Kim K, Chapman-Novakofski K, McAuley E, Woods JA. Higher antibody, but not cell-mediated, responses to vaccination in high physically fit elderly. J Appl Physiol 102: 1090–1098, 2007.[Abstract/Free Full Text]
  15. Kohut ML, Cooper MM, Nickolaus MS, Russell DR, Cunnick JE. Exercise and psychosocial factors modulate immunity to influenza vaccine in elderly individuals. J Gerontol A Biol Sci Med Sci 57: M557–M562, 2002.[Abstract/Free Full Text]
  16. Lancaster GI, Halson SL, Khan Q, Drysdale P, Wallace F, Jeukendrup AE, Drayson MT, Gleeson M. Effects of acute exhaustive exercise and chronic exercise training on type 1 and type 2 T lymphocytes. Exerc Immunol Rev 10: 91–106, 2004.[Web of Science][Medline]
  17. Lundgren M, Persson U, Larsson P, Magnusson C, Smith CI, Hammarstrom L, Severinson E. Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol 19: 1311–1315, 1989.[Web of Science][Medline]
  18. Ministry of Health, Labor and Welfare. Comprehensive. evaluation of tuberculosis. Ministry of Health, Labor and Welfare Database [Online], 2004, Tokyo, Japan. http://www.mhlw.go.jp/wp/seisaku/jigyou/04sougou/1-5-1html.
  19. Mosmann T, Cherwinski HR, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136: 2348–2357, 1986.[Abstract]
  20. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more [see comments]. Immunol Today 17: 138–146, 1996.[CrossRef][Web of Science][Medline]
  21. Nakayama K, Monma M, Fukushima T, Ohrui T, Sasaki H. Tuberculin responses and risk of pneumonia in immobile elderly patients. Thorax 55: 867–869, 2000.[Abstract/Free Full Text]
  22. Ng WY, Thai AC, Lui KF, Yeo PP, Cheah JS. Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients. Diabetes Res Clin Pract 43: 127–135, 1999.[CrossRef][Web of Science][Medline]
  23. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G, de Waal Malefyt R, de Vries JE. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 90: 3730–3734, 1993.[Abstract/Free Full Text]
  24. Rentenaar RJ, Gamadia LE, van DerHoek N, van Diepen FN, Boom R, Weel JF, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ. Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection J Clin Invest 105: 541–548, 2000.[Web of Science][Medline]
  25. Skapenko A, Leipe J, Niesner U, Devriendt K, Beetz R, Radbruch A, Kalden JR, Lipsky PE, Schulze-Koops H. GATA-3 in human T cell helper type 2 development. J Exp Med 199: 423–428, 2004.[Abstract/Free Full Text]
  26. Smith TP, Kennedy SL, Fleshner M. Influence of age and physical activity on the primary in vivo antibody and T cell-mediated responses in men. J Appl Physiol 97: 491–498, 2004.[Abstract/Free Full Text]
  27. Sousa AO, Henry S, Maroja FM, Lee FK, Brum L, Singh M, Lagrange PH, Aucouturier P. IgG subclass distribution of antibody responses to protein and polysaccharide mycobacterial antigens in leprosy and tuberculosis patients. Clin Exp Immunol 111: 48–55, 1998.[CrossRef][Web of Science][Medline]
  28. Steensberg A, Toft AD, Bruunsgaard H, Sandmand M, Halkjaer-Kristensen J, Pedersen BK. Strenuous exercise decreases the percentage of type 1 T cells in the circulation. J Appl Physiol 91: 1708–1712, 2001.[Abstract/Free Full Text]
  29. Tsuji I, Tamagawa A, Nagatomi R, Irie N, Ohkubo T, Saito M, Fujita K, Ogawa K, Sauvaget C, Anzai Y, Hozawa A, Watanabe Y, Sato A, Ohmori H, Hisamichi S. Randomized controlled trial of exercise training for older people (Sendai Silver Center Trial; SSCT): study design and primary outcome. J Epidemiol 10: 55–64, 2000.[Medline]
  30. Widhe M, Ekerfelt C, Forsberg P, Bergstrom S, Ernerudh J. IgG subclasses in Lyme borreliosis: a study of specific IgG subclass distribution in an interferon-gamma-predominated disease. Scand J Immunol 47: 575–581, 1998.[Web of Science][Medline]
  31. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89: 587–596, 1997.[CrossRef][Web of Science][Medline]




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