Neonatal immunization with insulinoma-released exosomes induces humoral immune response that protects islets from autoimmune pathogenesis (THER5P.835)

Abstract

Abstract Exosomes (EXOs) are immunostimulatory microvesicles that can activate both innate and adaptive immunity. We have demonstrated that autoreactive B and T cells in prediabetic non-obese diabetic (NOD) mice can recognize EXOs released by insulinoma. In this study, we examined EXO-specific humoral immune response and its contribution to the islet-specific autoimmunity. We immunized NOD neonates with EXOs, in which mature T cells are rare, and then monitored antibody and B cell responses to EXOs in 4- or 8-week-old mice. At 4 weeks, the immunized mice showed increased B cells in pancreatic lymph nodes but not in spleen as compared with untreated mice. EXO-specific serum Ig titers remained higher than the controls. At 8 weeks, the immunized group had higher IgG1 but lower IgG2a and increased expression of FoxP3 and PD1 on Th cells, suggesting a Th1/Th2 shift and induction of regulatory T cells. As a result, the neonatal-immunized mice remained insulitis-free till 8-week old, whereas, age/gender-matched control mice developed insulitis. This effect can be partially explained by the induction of protective, EXO-specific antibodies, since the immunized sera were inhibitory for CD86 expression on activated B cells, more efficient than control sera and in vivo, the sera protected islets from insulitis caused by diabetogenic T cells. Thus, EXOs may contain unique antigen(s) that could be used as neonatal vaccine to prevent autoimmunity.