PNNL

Abstract

Understanding of the immune mechanisms that lead to rejection versus tolerance of al-logeneic pancreatic islet grafts is of paramount importance, as it facilitates the develop-ment of innovative methods to improve the transplant outcome. Here, we used our estab-lished intraocular islet transplant model to gain novel insight into changes in the local metabolome and proteome within the islet allograft’s immediate microenvironment in association with immune-mediated rejection or tolerance. We performed integrated metabolomics and proteomics analyses in aqueous humor samples representative of the graft’s microenvironment under each transplant outcome. The results showed that several free amino acids, small primary amines, and soluble proteins related to the Warburg effect were upregulated or downregulated in association with either outcome. In general, the observed shifts in the local metabolite and protein profiles in association with rejection were consistent with established pro-inflammatory metabolic pathways; and those ob-served in association with tolerance were immune regulatory. Taken together, the current findings further support the potential of metabolic reprogramming of immune cells to-wards immune regulation through targeted pharmacological and dietary interventions against specific metabolic pathways that promote the Warburg effect to prevent the rejec-tion of transplanted islets and promote their immune tolerance.