Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Diet-Induced Obesity Results In Lymphatic Dysfunction And Impaired T Cell Function
Nicholas J. Albano, BS, Daniel A. Cuzzone, MD, Swapna Ghanta, MD, Seth Z. Aschen, BS, Ira L. Savetsky, MD, Jason C. Gardenier, MD, Walter J. Joseph, BS, Jeremy S. Torrisi, BA, Babak J. Mehrara, MD, Gina T. Farias-Eisner, BA.
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Introduction:
Obesity induced inflammation is a major contributor to morbidity from a variety of disorders including atherosclerosis, cancer, and metabolic syndrome. Although many studies have focused on the cardiovascular effects of obesity, the negative effects of dietary changes on the lymphatic system remain largely unknown. This gap in our knowledge is important since the lymphatic system is a critical physiologic regulator of inflammatory responses, a key mechanism by which the negative effects of obesity are exerted. We have previously shown that obesity results in significant architectural changes in peripheral lymph nodes. The purpose of these experiments was to determine the functional effects of these changes on immune responses.
Methods:
We used a well-described diet induced obesity (DIO) model in which adult male C57BL/6J mice were fed a high fat (60%) and compared with control mice fed a normal chow diet for 10 weeks. To test humoral immunity, we vaccinated DIO or control mice with ovalbumin (OVA) and analyzed serum anti-OVA IgG1 titers 3 weeks after vaccination. Additionally, B and T cells were isolated from peripheral lymph nodes, cultured, and re-stimulated in vitro to analyze cytokine responses using ELISA. To assess cellular immunity, we induced contact hypersensitivity responses in the ear using 1-fluoro-2,4-dinitrobenzene (DNFB). Responses were measured using caliper measurements, immunohistochemistry and flow cytometry to analyzed gross and cellular inflammatory responses, respectively. Finally, we analyzed inflammatory lymph node lymphangiogenesis in obese and control animals to determine how draining lymph nodes respond to inflammatory stimuli.
Results:
Consistent with our previous studies, we found that DIO mice had significantly smaller lymph nodes as compared with controls; however, despite these changes, DIO mice demonstrated comparable anti-OVA IgG1 titers and B cell cytokine production as compared with controls. In contrast, T cells isolated from DIO mice demonstrated a significant decrease in both interferon gamma (IFN-g) and IL4 production after stimulation in vitro (P<0.05 for both). Further supporting changes in T cells in response to obesity was our finding of increased contact hypersensitivity responses to DNFB. In these experiments, obese mice displayed a significant increase in peak inflammation (160% increase) as compared to controls. More importantly, we found that obese mice required a much longer period of time to clear inflammatory responses as compared with controls (11.75 vs. 8.2 days; p<0.05). Finally, although we found only modest changes in inflammatory lymph node lymphangiogenesis, we found significant changes in T cell populations in DIO mice as compared to controls (P=0.0003).
Conclusions:
This study is the first to show that DIO results in significant architectural and functional changes in lymph nodes and lymphatic regulation of inflammation. Although the B cell responses were relatively unchanged by obesity, we found that DIO results in exaggerated T cell inflammation and impaired T cell memory responses. These changes not only increase the intensity of inflammation but, more importantly for the pathology of obesity, impair its resolution. This finding is critical and suggests that pathologic changes in the lymphatic system may exacerbate and contribute to the wide-ranging pathologic responses to obesity.


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