Advancing Transplantation Tolerance in Nonhuman Primates

While short-term outcomes following organ transplant have greatly improved with the development of more effective immunosuppression, long-term outcomes remain problematic with a significant number of patients developing diabetes, accelerated heart disease as well as increased rates of cancers and infections. For decades transplant researchers and clinicians have sought to develop strategies to induce immune tolerance to transplanted organs and avoid the requirement for life-long immunosuppression. It is likely that any successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation blockade. One of the most important interactions is the CD40-CD154 pathway. We will evaluate novel, clinically relevant therapeutics targeting either CD40 or CD154 and explore their role in facilitating tolerance. Based on our recent publication showing that CD11b is a novel alternate receptor for CD154 during alloimmunity, we will also test novel nanotechnology to block the CD154:CD11b interaction, an important mechanism of cross-talk between the innate and adaptive immune responses during transplantation. Moreover, based on our published data showing that memory T cells are a potent barrier to transplantation tolerance, we will determine the role of OX40-OX40L blockade to control alloreactive memory CD8+ T cells and promote a pro-regulatory environment. In addition, we will assess the importance of the VISTA pathway on the induction of donor-specific tolerance using an agonistic anti-human VISTA antibody. VISTA has a dual role in negatively regulating antigen-specific T cell responses while also impacting the innate immune response by inhibiting ischemia reperfusion injury, monocyte activation and neutrophil migration thereby suppressing the early inflammatory response. We will also investigate the contribution of IL-1 and the inflammasome on tolerance induction and employ clinically applicable therapeutics to control early inflammation during the induction of tolerance. The combination of cellular therapy and costimulation blockade is a powerful strategy to promote donor-specific tolerance. Myeloid derived suppressor cells (MDSCs) have inherent immunosuppressive properties and have been used to facilitate tolerance. They modulate innate immunity and inhibit T cell activation and effector cell function while also promoting regulatory T cell expansion for maintenance of long-term donor specific tolerance. Apoptotic donor leukocytes (ADLs) represent another promising cellular therapy that has been proven to control alloreactive T cells and promote donor specific T cell deletion. We will use donor bone marrow derived MDSCs or ADLs in combination with the above novel therapeutics to promote tolerance in nonhuman primate kidney transplantation.