Omar R. Fagoaga

Influence of Obesity on Immune Function

OBJECTIVE To compare immune function in obese and nonobese subjects. DESIGN Obese and nonobese subjects were compared cross-sectionally. To test for the influence of other factors on immunity, aerobic fitness, psychological well-being, and serum levels of glucose, triglycerides, and cholesterol were measured and included in multiple regression models to determine their comparative effects. SUBJECTS/SETTING Community-based subjects included 116 obese women (age = 44.3 +/- 9.7 years, body mass index = 33.2 +/- 6.5) and 41 nonobese women (age = 42.2 +/- 10.9 years, body mass index = 21.2 +/- 1.9). STATISTICAL ANALYSES PERFORMED Independent t tests, Pearson product moment correlations, and stepwise multiple regression procedures. RESULTS Obesity was linked to elevated leukocyte and lymphocyte subset counts (except for natural killer and cytotoxic/suppressor T cells), suppressed mitogen-induced lymphocyte proliferation (an index of T- and B-cell function), higher monocyte and granulocyte phagocytosis and oxidative burst activity, and normal activity of natural killer cells. APPLICATIONS/CONCLUSIONS These data support the contention that obesity is associated with alterations in immune function. Further research is needed to link immunosuppression with the previously reported elevated risk of infection among the obese.

Influence of mode and carbohydrate on the cytokine response to heavy exertion.

OBJECTIVE AND METHODS This randomized, double-blind, placebo-controlled study was designed to determine the influence of exercise mode and 6% carbohydrate (C) versus placebo (P) beverage ingestion, on blood cell counts, plasma glucose, hormone, and inflammatory cytokine responses (five total samples over 9 h) to 2.5 h of high-intensity running and cycling (approximately 75% VO2max) by 10 triathletes who acted as their own controls. Statistical significance was set at P < or = 0.05. RESULTS C relative to P ingestion (but not exercise mode) was associated with higher plasma levels of glucose and insulin, lower plasma cortisol and growth hormone, and diminished perturbation in blood immune cell counts. The pattern of change over time for interleukin (IL)-6 was significantly different between C and P conditions (P = 0.021) and between running and cycling modes (P < 0.001), with the lowest postexercise values seen in the C-cycling sessions (10.7 +/- 1.8 pg x mL(-1)) and the highest in the P-running sessions (51.6 +/- 14.2 pg x mL(-1)). The pattern of change over time between C and P conditions (but not modes) was significantly different for IL-1 receptor antagonist (P = 0.003), with values once again lowest for the C-cycling sessions (1.5 h postexercise, 301 +/- 114 pg x mL(-1)) and highest for the P-running sessions (1171 +/- 439 pg x mL(-1)). CONCLUSION These data indicate that carbohydrate versus placebo ingestion (4 mL x kg(-1) carbohydrate or placebo every 15 min of the 2.5-h exercise bout) is associated with higher plasma glucose levels, an attenuated cortisol response, and a diminished pro- and anti-inflammatory cytokine response.

Immune function in marathon runners versus sedentary controls

Marathon runners (N = 22) who had completed at least seven marathons (X +/- SEM = 23.6 +/- 5.7) and had been training for marathon race events for at least 4 yr (12.3 +/- 1.3) were compared with sedentary controls (N = 18). Although the two groups were of similar age (38.7 +/- 1.5 and 43.9 +/- 2.2 yr, respectively) and height, the marathon runners were significantly leaner and possessed a VO2max 60% higher than that of the controls. Neutrophil counts tended to be lower in the group of marathoners, while other leukocyte and lymphocyte subsets were similar to controls. Mitogen-induced lymphocyte proliferation did not differ between groups. Natural killer cell cytotoxic activity (NKCA) was significantly higher in the marathoners versus controls (373 +/- 38 vs 237 +/- 41 total lytic units, respectively, a 57% difference, P = 0.02). For all subjects combined (N = 40) and within the group of marathon runners (N = 22), percent body fat was negatively correlated with NKCA (r = -0.48, P = 0.002; r = -0.49, P = 0.019, respectively), and age was negatively correlated with Con A-induced lymphocyte proliferation (r = -0.41, P = 0.009; r = -0.53, P = 0.011, respectively). These data indicate that NKCA but not mitogen-induced lymphocyte proliferation is higher in marathon runners relative to sedentary controls.

Immune response to exercise training and/or energy restriction in obese women.

PURPOSE The effect of exercise training (five 45-min walking sessions/wk at 60-75% maximum heart rate) and/or moderate energy restriction (4.19-5.44 MJ or 1,200-1,300 kcal x d(-1)) on innate and adaptive immunity (including mitogen-stimulated lymphocyte proliferation (MSLP), natural killer cell activity (NKCA), and monocyte and granulocyte phagocytosis and oxidative burst (MGPOB) was studied in obese women (N = 91, age 45.6 +/- 1.1 yr, body mass index 33.1 +/- 0.6 kg x m(-2)) randomized to one of four groups: control (C), exercise (E), diet (D), exercise, and diet (ED). METHODS Aerobic power, body composition, and immune function were measured in all subjects before and after a 12-wk diet intervention period, with data analyzed using a 4 x 2 repeated measures design. All subjects self-reported symptoms of sickness in health logs using a precoded checklist. Statistical significance was set at P < or = 0.05. RESULTS Data from this study indicate that although exercise training was unrelated to any significant changes in resting immune function, the number of days with symptoms of upper respiratory tract infection (URTI) was reduced relative to subjects in the nonexercise groups (5.6 +/- 0.9 and 9.4 +/- 1.1 sickness days, respectively, P < 0.05). Energy restriction and weight loss (7.9 +/- 0.7 kg) was associated with a significant decrease in MSLP, but no change in NKCA, MGPOB, or URTI. CONCLUSION The data are consistent the viewpoint that weight loss, even at a moderate rate, is associated with a decrease in mitogen-stimulated lymphocyte proliferation without a change in various measures of innate immunity of the blood compartment.

Influence of photoperiod on immune cell functions in the male Siberian hamster

The present study tested the hypothesis that immune cell function is influenced by ambient photoperiod. The male Siberian hamster served as the experimental model because day length regulates a variety of seasonal adaptations in physiology. Adult hamsters were in long days (16 h of light daily), which sustains gonadal function, or transferred to short days (8 h) for >4 wk to induce testes regression. Blood was drawn from the ocular sinus or splenocytes obtained to assess basal indexes of immune cell function. In hamsters in short days, natural killer cell cytolytic capacity, as well as spontaneous blastogenesis in both whole blood and isolated lymphocytes, were enhanced compared with that in hamsters in long days. By contrast, phagocytosis and oxidative burst activity by both granulocytes and monocytes were suppressed in hamsters by exposure to short days versus long days. Selective changes in immune cell function coincided with short-day-induced gonadal atrophy. These findings raise the hypothesis that photoperiod regulation of physiological adaptations, including distinct immune cell functions, may help individuals anticipate seasonal challenges posed by opportunistic diseases or climate to facilitate survival.

Carbohydrate affects natural killer cell redistribution but not activity after running.

This randomized, double-blind, placebo-controlled study was designed to determine the influence of carbohydrate supplementation on the natural killer cell response to 2.5 h of high-intensity running (76.7 +/- 0.4% VO2max). Thirty experienced marathon runners (VO2max 53.4 +/- 1.0 mL x kg[-1] x min[-1], age 41.5 +/- 1.4 yr) were randomized into carbohydrate supplement (N = 17) and placebo (N = 13) groups. Subjects rested for 10-15 min before a blood sample at 0715, and then ingested 0.75 L of carbohydrate beverage (Gatorade) or placebo. At 0730, subjects began running at 75-80% VO2max for 2.5 h and drank 0.25 L of carbohydrate or placebo fluid every 15 min. Immediately after the 2.5 h run (1000), another blood sample was taken, followed by 1.5 h, 3 h, and 6-h recovery samples. Carbohydrate supplementation versus placebo had a significant effect on the pattern of change in glucose, cortisol, and the blood concentration of natural killer cells ([F (4,25) = 3.79, P = 0.015], but not natural killer cell activity following 2.5 h of intensive running.

Saliva immunoglobulins in elite women rowers.

Abstract Saliva immunoglobulins (sIgA, sIgG, and sIgM) and upper respiratory tract infection (URTI) rates were evaluated in 20 elite female rowers and 19 nonathletes. Also, the influence of carbohydrate versus placebo beverage consumption on saliva immunoglobulin responses to rowing training sessions was measured in 15 rowers and in 5 non-exercising rowers. Saliva samples were collected 1 day before, and 5–10 min and 1.5 h after rowing or rest. Pre-exercise sIgA (but not sIgG or sIgM) concentration was 77% higher in the rowers compared to nonathletes (P < 0.001). Health records kept over 2 months revealed mean 5.2 (SEM 1.2) and 3.3 (SEM 1.1) days with URTI symptoms for the rowers and controls, respectively. For all 39 subjects, and for the 20 rowers separately, no significant correlation was found between URTI symptoms or insulin, cortisol, and growth hormone concentrations and pre-exercise or exercise-related changes in saliva immunoglobulin concentrations or secretion rates. The patterns of change in saliva immunoglobulin concentration and secretion rate did not differ between the carbohydrate and placebo rowing trials, or between exercised and rested athletes. These data indicated an increased sIgA concentration in the female elite rowers compared to the nonathletes, no association between saliva immunoglobulins and URTI, and no effect of a normal 2-hour training session or carbohydrate ingestion on saliva immunoglobulin concentrations or secretion rates.

The role of anti-pig antibody in pig-to-baboon cardiac xenotransplant rejection.

The role of naturally produced antibody in discordant xenograft rejection is still uncertain. Twelve or-thotopic pig-to-baboon heart transplants (HTx) were performed. In 2 baboons, no antibody adsorption (AbA) was performed. In 5 baboons, AbA with a pig lung was performed during circulatory arrest. In 5 baboons, AbA and blood exsanguination at the beginning of cardiopulmonary bypass (CPB) were performed. Baboons were divided into 2 groups; group 1 (n=4) died within 24 hr of HTx and group 2 (n=8) survived more than 24 hr. Mean survival period was 9.8±3.0 hr in group 1 and 151±33 hr in group 2. Baboon anti-pig antibody (Ab) was measured before CPB, before circulatory arrest, during AbA, at the end of CPB, and daily after HTx. Anti-RBC Ab was measured by the titration method at temperatures of 4°C and 37°C (RAb-4 and RAb-37). Anti-endothelial cell Ab (EAb) and anti-white blood cell Ab (WAb) titers were measured with ELISA. RAb titration ≥l/4 and EAB and WAb ≥ 1/256 were determined to be seropositive (S(+)). S(+) rate of RAb-37 at the end of CPB (endCPB) in group 2 was significantly higher than that in group 1 (8/8 vs. 1/4; P<0.05). The seronegative (S(-)) rates of RBC-4 and EAb (endCPB) in group 2 were higher than those in group 1 (7/8 vs. 1/4 and 6/8 vs. 1/4, respectively), but not significantly. There was no difference in S(-) rate of WAb (endCPB) between group 1 and group 2. More than 4-fold decrease in RAb-4 and RAb-37 by AbA with a pig lung was observed in 5 and 7 of 8 baboons, while EAb and WAb did not change by AbA. In all of group 2, RAb-4 reverted to S(+) within 3 days after HTx. One baboon had no rejection episode and died of infection 16 days after HTx (baboon 16); however, it also became S(+) for RAb-4 a day after HTx until death. In 4 of group 2, RAb-37 became S(+) 1 or 2 days before death by rejection. Baboon 16, however, became S(+) for RAb-37 7 days after HTx and S(-) again 9 days after HTx until death. EAb became S(+) in all of group 2, but 5 of them survived more than 5 days after seroconver-sion. It was concluded that a pig lung absorbed RAb-4 and RAb-37 but not EAb or WAb, and that RAb, especially RAb-37, may play a role in discordant xenograft rejection.

Predictive value of human leucocyte antigen epitope matching using HLAMatchmaker for graft outcomes in a predominantly African-American renal transplant cohort.

Abstract: The HLAMatchmaker program is based on the donor/recipient comparison of the polymorphic triplet amino‐acid sequences of the antibody‐accessible regions on the human leucocyte antigen (HLA) molecule. The previous reports on its predictive value for renal allograft outcomes are conflicting. We conducted a retrospective study in a predominantly African‐American (AA) cohort (N=101, 94% AA). HLA typing was performed by molecular methods and triplet matching using HLAMatchmaker. Study end points included graft survival and incidence of acute rejection. The relationship between the number of triplet mismatches (TMM) and the degree of HLA antigen MM was evaluated using Pearsons correlation coefficient. Logistic regression models were used to examine the association between triplet matching and the study end points. Kaplan–Meier and Cox proportional hazard models were used for graft survival analysis. The strongest relationship between the number of TMM and HLA antigen MM was observed for HLA‐DQ (r=0.88). The association between triplet matching at HLA‐A, ‐B, ‐DR and ‐DRw HLA loci and the study end points was not statistically significant. However, after grouping, the unadjusted estimates of graft survival for those with more than 10 Class I TMM were significantly worse than the others (p=0.03). Adjusting for the effect of donor source, recipient characteristics and the immunosuppressive regimen did not change this association (hazard ratio=0.2, confidence interval=0.04–1.1). We conclude that triplet matching using HLAMatchmaker can provide useful prognostic information in kidney transplantation and that more than 10 donor/recipient Class I HLA TMM is predictive of worse graft outcome.

Reproductive, Neuroendocrine, and Immune Consequences of Acute Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in the Siberian Hamster

Abstract The present study tested the hypothesis that acute treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impairs fertility, disrupts the nocturnal melatonin rhythm, and suppresses lymphocyte function. Adult Siberian hamsters administered 2 or 100 μg TCDD/kg body weight/0.2 ml sesame oil had a delayed latency to first litter and an increased adult mortality compared to hamsters given 0.1 μg/kg or vehicle. Within 75 days of TCDD treatment, full reproductive capabilities were achieved. Moreover, the nocturnal melatonin rhythm was not disrupted in adults administered TCDD or in their progeny. Lymphocyte activity varied with respect to time of day and treatment. Lymphocyte proliferation was enhanced at night irrespective of TCDD treatment; during the day, 2 wk after the 2-μg/kg treatment, blastogenesis was reduced compared to that in the 0.1-μg/kg group or in vehicle-treated controls. In contrast, TCDD did not affect the mixed lymphocyte reaction in response to allogeneic antigen when assessed at 2 and 20 wk post-treatment. Thus, findings indicate that TCDD produced acute effects on fertility, mortality, and systemic lymphocyte proliferation, but long-lasting effects on specific aspects of reproductive, neuroendocrine, and immune cell functions were not observed.