Engineering synthetic suppressor cells for immune protection of transplanted islet beta cells

About This Grant

Project Summary Therapies for insulin-dependent diabetes remain inadequate. Islet cell transplantation using donor islets or stem cell-derived tissue could revolutionize treatment, but preventing immune rejection of the transplanted beta cells remains a critical unsolved issue. Current approaches focus on editing hypoimmune islets or redirecting T regulatory suppressor cells, two exciting but challenging strategies. As a novel and more flexible approach, we recently developed synthetic suppressor T cells that use engineered synNotch receptors to sense local disease signals and, in response, induce the targeted expression and delivery of customized immune suppressive payloads. These synthetic suppressor cells are capable of locally targeted immune suppression, without systemic suppression. Our goal is to design optimal therapeutic suppressor cells that can protect transplanted islets by locally blocking immune rejection and promoting tolerance. The flexibility of this platform allows us to systematically explore what payloads and other cell modifications result in the most effective and durable immune protective behaviors. Our aims are: Aim 1. Systematically screen combinatorial suppressive payloads to identify those that yield synthetic suppressor cells that can effectively block key components of cell-mediated rejection (CD4+, CD8+, CD4+Th17, NK, B) and humoral mediated rejection (e.g. complement). Combinations will then be tested for ability to protect islets in several in vivo immune rejection models. Programs will be triggered by synNotch receptors that detect antigens specifically on the beta cell surface, including targets like GLP1R. Aim 2. Introduce modifications to synthetic suppressor cells to increase their survival and persistence, including versions of growth and survival cytokines designed to function in a fully autocrine manner (i.e. cause synthetic suppressor cells to survive without inducing proliferation/inflammation via other immune cells). These survival signals will be induced in a local manner via Islet-sensing synNotch receptors. Suppressor cells with these modifications will be tested for improved persistence in islet immune protection. Aim 3. Engineer synthetic suppressor cells to take up residence in islets by engineering them with chimeric synthetic cell adhesion molecules that recognize islet antigens. Together, these aims should yield optimized suppressor cells that are strongly retained in islets, durably persist only in islets, and produce combinatorial suppressive payloads that prevent immune rejection. This work will yield a better fundamental understanding of immune rejection and the requirements for immune protection and would yield approaches to local immune suppression relevant to solid organ transplantation and autoimmune disease.