Metabolic factors mediating alloimmunity

• Applicant: Dr. Markus Quante
• Subject Area: General and Visceral Surgery
• Term: from 2015 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 278469292

The global prevalence of obesity has reached epidemic proportions. A recent study assessing global and national data of obesity reports on alarming numbers of obesity in Germany with close to 50% of women and more than 60% of men being either overweight or obese. Recent evidence has conceptualized obesity as a chronic inflammatory condition impacting numerous disease processes, and, in organ transplantation some clinical reports have shown more frequent acute rejections in addition to an augmented allograft immunogenicity in obese recipients. Although it is known that obesity promotes inflammation, very little is known on its impact on alloimmune responses. Intriguingly, increasing evidences suggest that bariatric surgery alters metabolism with potential anti-inflammatory capacities. We have accumulated convincing in-vivo data that demonstrate a significant impact of obesity and bariatric surgery on transplant survival. Our results indicate that obese mice exhibit a more rapid graft rejection linked to a significant increase in IFN-g expression in splenic CD4+ and CD8+ T-cells; increased IFN-g responses in EliSpot assays documented an augmented alloreactivity in obese compared to lean controls. Furthermore, obese animals that underwent bariatric surgery demonstrated significantly prolonged allograft survival beyond that observed in both, obese and lean animals. Prolonged graft survival subsequent to bariatric surgery was linked to a dramatic decline in IFN-g expression, significantly increased IL-10 expression and reduced alloreactivity. Next, quantitative metabolomic profiling was performed and identified biomarkers and metabolic pathways that could be involved in mediating the interplay of obesity, bariatric surgery and immune responses. Out of 290 metabolites analyzed, we have now identified three promising candidates with significant statistical impact by ANOVA, heat mapping and significance analysis of microarrays. Strikingly, the use of a candidate related to bile acid metabolism resulted in prolonged allograft survival in obese animals. We have everything in place to further explore the impact and in-depth mechanisms of additional metabolites on the immune response and allograft survival in our established animal models. Our current application builds upon the overall hypothesis that metabolic factors are mediating the impact of obesity and bariatric surgery on the immune response by acting on CD4+ and CD8+ T cells, either skewing them towards a pro-inflammatory profile in obesity or towards Th2-dominated conditions subsequent to weight loss. Thus, our goal is to elucidate metabolic factors and related mechanisms by which obesity induces inflammation while bariatric surgery is communicating a prolongation of graft survival. Our study will identify novel mechanisms and targets with a high translational potential to i) treat the pro-inflammatory consequences of obesity and ii) to identify novel pathways of immunosuppression.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Stefan Tullius, Ph.D.