Diet-induced obesity impairs both innate and adaptive immune responses.

A60

Obesity increases the risk of several solid tumors, including breast, prostate, pancreatic, and colon. One of several mechanisms that may underlie the relationship between obesity and tumor risk is an obesity-induced impairment in immune function; however, little work has been done to examine which components of the immune system are adversely impacted by obesity. Therefore, the goal of this study was to evaluate the effect of different levels of adiposity on innate and adaptive immune responses. Female, C57BL/6 mice were fed one of the following diets to generate cohorts of mice with increasing levels of adiposity: 1) 30% calorie restricted diet (formulated such that the reduction in calories was entirely from carbohydrates) 2) 10% kcal from fat diet fed ad libitum; 3) 60% kcal from fat diet fed ad libitum. After 23 weeks on each diet, mice weighed 18.8+0.5, 27.4+0.8, and 33.6+2.2 grams, and had 23.7+1.1%, 29.6+0.8% and 47.8+3.2% body fat, respectively. Thus, mice in groups 1, 2, and 3 were characterized as lean, overweight and obese. To induce antigen-specific immune responses in lean, overweight, and obese animals (n=12/group), mice received a primary vaccination at week 17 with a recombinant vaccinia/fowlpox vector containing genes encoding LacZ and GMCSF; and booster vaccinations at 19 and 21 weeks with a recombinant fowlpox vector containing genes encoding LacZ and GMCSF. This vaccine platform was chosen because it is similar to many of the therapeutic cancer vaccines used by our laboratory in clinical trials. Spleens, inguinal lymph nodes, and sera were collected two weeks following the last immunization (week 23) for assessment of innate and antigen-specific immune responses. Obesity and overweight significantly reduced natural killer (NK) cell function, increased the number of macrophages and reduced Con A-induced CD4⁺ T cell proliferation in the spleen (P<0.05). With respect to adaptive-immune responses, obesity (but not overweight) significantly reduced β-gal specific total and IgG_2a antibody titers and β-gal specific CD4⁺ T cell proliferation (P<0.05); while both obesity and overweight reduced β-gal specific interferon-γ production. These results demonstrate that both adaptive and innate immunity are impaired by overweight and obesity and suggest that the immunological response to common vaccinations (e.g. flu, tetanus, etc) may be significantly impaired by obesity. Furthermore, the innate and adaptive immune deficits observed in overweight and obesity may partly explain the increased risk of tumor development humans with increasing adiposity, and need to be explored in future studies.