High fat diet drives rapid production of donor specific antibody in heart transplantation 2307505

Abstract Introduction Solid organ transplantation is the most effective curative treatment for end-stage organ failure and while immunosuppression regimens have drastically improved graft survival by blocking acute cellular rejection, both acute and chronic antibody mediated rejection (ABMR) remain key mediators of graft loss. Donor specific antibody (DSA) is produced by plasma cells (PC) generated through germinal center (GC)-dependent or independent mechanisms. We hypothesized that in obesity GC-independent or extrafollicular (EF) pathways are increased leading to more rapid production of DSA. Methods C57BL/6 mice received HFD or control diet for four weeks prior to receiving Balb/c heart allografts. DSA was measured by crossmatch assay of serum with donor thymocytes. Animals were sacrificed at 5- and 14-days post transplantation. Splenic immune cell composition and function was analyzed by flow cytometry and immunohistochemistry. Graft infiltrating cells and complement deposition were measured by histology. Results Relative to control diet, mice on HFD had increased B cell activation at day 5 post-transplant and an increase in serum DSA with canonically EF IgG subtypes compared with canonically GC-dependent subtypes. At 14 days post-transplant mice on HFD had markedly increased total and donor specific splenic PCs which roughly correlated to their weight. Spleens of HFD mice had no increase in GC B cells and fewer follicular helper T cells. Therefore, we inferred that high fat diet enhances DSA PC generation through GC-independent or EF pathways. Conclusion DSA from EF PCs is less dependent on T cell derived signals and therefore less sensitive to traditional immunosuppression. We observed that PCs generated in response to transplant and immunization in mice on HFD have distinct metabolic profiles including increased oxidative phosphorylation and fatty acid oxidation and mitochondrial activity. These data suggests that targeting PC metabolism therapeutically or prophylactically will reduce DSA and ameliorate ABMR. Funding Source n/a Topic Categories Transplantation Immunology (TRAN)