Safe Non-Myeloablative Allogeneic HSCT for Autoimmune Diabetes Using Donor Derived Veto Cells

Abstract

The induction of partial tolerance towards pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM), can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune TCR repertoire is associated with a substantial risk for transplant related mortality. Here, we demonstrate in the NOD mouse model for T1DM a safe transplant modality using allogeneic non-myeloablative T cell depleted HSCT in conjunction with donor derived veto cells. Thus, marked chimerism is attained without any transplant-related mortality, and with a very high rate of diabetes prevention. T cell receptor sequencing of transplanted mice shows marked changes in the T cell repertoire and in the prevalence of specific autoimmune T cell clones. Taken together, our results demonstrate a proof of concept for the treatment of T1DM using veto cell-based TD-HSCT.