Adjuvant conditioning induces an immunosuppressive milieu that delays alloislet rejection through the expansion of myeloid-derived suppressor cells

Abstract

Advances in immunosuppression have been relatively stagnant over the past 2 decades, and transplant recipients continue to experience long-term morbidity associated with immunosuppression regimens. Strategies to reduce or eliminate the dosage of immunosuppression medications are needed. We discovered a novel administration strategy using the classic adjuvant alum to condition murine islet transplant recipients, known as adjuvant conditioning (AC), to expand both polymorphonuclear and monocytic myeloid-derived suppressive cells (MDSCs) in vivo. These AC MDSCs potently suppress T cell proliferation when cultured together in vitro. AC MDSCs also facilitate naïve CD4+ T cells to differentiate into regulatory T cells. In addition, we were able to demonstrate a significant delay in alloislet rejection compared with that by saline-treated control following adjuvant treatment in a MDSC-dependent manner. Furthermore, AC MDSCs produce significantly more interleukin (IL)-10 than saline-treated controls, which we demonstrated to be critical for the increased T cell suppressor function of AC MDSCs as well as the observed protective effect of AC against alloislet rejection. Our data suggest that adjuvant-related therapeutics designed to expand MDSCs could be a useful strategy to prevent transplant rejection and curb the use of toxic immunosuppressive regimens currently used in transplant patients.