Transplantation is the preferred treatment for patients suffering from end-stage kidney disease. While short- term outcomes have greatly improved with the development of more effective immunosuppression, the long- term outcomes remain problematic with life-span limiting complications including 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. Transplantation tolerance is typically defined as the lack of a donor-directed immune response while preserving protective immunity in the absence of long-term immunosuppression. It is likely that any successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation blockade. Two of the most promising reagents are anti-CD154 and anti-OX40L, both of which are protolerogenic and supportive of immunoregulation as part of their mechanism of action. We have partnered with industry to evaluate two clinically relevant compounds, dazodalibep (HZN-4920) an innovative anti-CD154 nonantibody scaffold protein and a high affinity, novel anti-human OX40L antibody. 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. 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. We will use donor bone marrow derived MDSCs in combination with novel therapeutics to control naïve (anti-CD154, anti-VISTA) and memory (anti-OX40L) T cell responses as well as the innate immune response (anti-VISTA) in combination with pro- tolerogenic anti-inflammatory cellular therapy (repetitive MDSC infusions). We will test this strategy in a clinically relevant nonhuman primate kidney transplant model.