*Purpose: Our earlier observations revealed release of exosomes from human islets containing microRNAs (miRNA) specific to islet stress and damage in vitro and in vivo after human-to-mouse xenoislet transplantation. Islet antigens including insulin, glutamic acid decarboxylase 65 (GAD65), Zinc Transporter 8 (ZnT8) induce autoimmunity in Type 1 Diabetes (T1D). In the context of islet auto- or allo-transplantation, we hypothesize that islet-derived exosomes may carry self-antigens resulting in induction of immune (auto- or allo-) responses, further contributing to islet graft rejection.

*Methods: Human islets were procured from Integrated Islet Distribution Program (IIDP). Exosomes were isolated using miRCURY exosome isolation kit. Self-antigen expression in exosomes was assessed by western blot. To assess whether islets release exosomes containing self-antigens under cellular stress, multiple low-dose streptozotocin (MLDS) induced insulitis mouse model was used. To assess whether islet-derived exosomes can induce an autoimmune response, C57BL6/J mice were immunized using control or MLDS exosomes (collected at day 10) (100 µg) (i.v. or with Freund’s complete adjuvant, followed by booster in incomplete adjuvant) for 21 days. Serum insulin autoantibody (IAA) level was assessed by ELISA.

*Results: Although control human islet derived exosomes contained GAD65 and CHGA, 24 h exposure to proinflammatory cytokines increased expression of exosomal GAD65 and differentially processed CHGA but not ZnT8 (Figure 1A-C). In vivo, at day 10 after MLDS regimen, peri-insulitis was evident, with circulating exosomes containing ZnT8 and CHGA but not GAD65. Exosome immunization induced mild insulin autoantibody response only in mice immunized using exosomes collected at day 10 after MLDS administration.

*Conclusions: Circulating exosomes containing islet antigens may induce autoimmunity. Further investigations are necessary to delineate contributions of islet-derived exosomes to islet graft rejection in the context of auto- or allo-transplantation.

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