Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in Type 1 Diabetes.

The effective suppression of adaptive immune responses is essential for the success of allogeneic cell therapies. In islet transplantation for Type 1 Diabetes, pre-existing autoimmunity provides an additional hurdle, as 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 are generally successful in suppressing alloimmune responses, but dramatically hinder the widespread adoption of this therapeutic approach and fail to control memory T cell populations, which leaves 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 escape, improve cell viability, and increase material compatibility are all approaches that can decrease the local release of antigen and danger signals into the implant microenvironment. Implant materials can be further enhanced through the local delivery of anti-inflammatory, suppressive, chemotactic, and/or tolerogenic agents, which serve to control both the innate and adaptive immune responses to the implant with a benefit of reduced systemic effects. Lessons learned from understanding how to manipulate allogeneic and autogenic immune responses to pancreatic islets can also be applied to other cell therapies to improve their efficacy and duration. STATEMENT OF SIGNIFICANCE: This review explores key immunologic concepts and critical pathways mediating graft rejection in Type 1 Diabetes, which can instruct the future purposeful design of immunomodulatory biomaterials for cell therapy. A summary of immunological pathways initiated following cellular implantation, as well as current systemic immunomodulatory agents used, is provided. We then outline the potential of biomaterials to modulate these responses. The capacity of polymeric encapsulation to block some powerful rejection pathways is covered. We also highlight the role of cellular health and biocompatibility in mitigating immune responses. Finally, we review the use of bioactive materials to proactively modulate local immune responses, focusing on key concepts of anti-inflammatory, suppressive, and tolerogenic agents.