Designing Biomaterials for the Modulation of Allogeneic and Autoimmune Responses to Cellular Implants in Type 1 Diabetes

Abstract

The effective suppression of the adaptive immune responses is essential for the success of allogeneic cell therapies. For islet transplantation for Type 1 Diabetes, pre-existing autoimmunity provides an additional hurdle, as the memory autoimmune T cells mediate both an autoantigen-specific attack on the donor beta cells and an alloantigen-specific attack on the donor graft cells. Immunosuppressive agents used for islet transplantation, while generally successful in suppressing alloimmune responses, dramatically hinder the widespread adoption of this therapeutic approach, while also failing to control the memory T cell populations, leaving the graft vulnerable to destruction. In this review, we highlight the capacity of biomaterials to provide local and nuanced instruction to suppress or alter immune pathways activated in response to an allogeneic islet transplant. Biomaterial immunoisolation is a common approach employed to block direct antigen recognition and downstream cell-mediated graft destruction; however, immunoisolation alone still permits shed donor antigens to escape into the host environment, resulting in indirect antigen recognition, immune cell activation, and the creation of a toxic graft site. Designing materials to decrease antigen shedding, improve cell viability, and increase material compatibility are all approaches that can decrease antigen shedding and danger signals in the implant microenvironment. Implant materials can be further enhanced through the local delivery of anti-inflammatory, suppressive, chemotactic, or tolerogenic agents, aimed at controlling both the innate and adaptive immune responses to the implant, with a benefit of reduced systemic effects. Lessons learned from the understanding how to manipulate allogeneic and autogenic immune responses to pancreatic islets can be applied to numerous other cell therapies to improve graft efficacy and duration.