Clinical islet transplantation (CIT), the infusion of allogeneic islets into the liver, has shown significant promise in the long-term treatment of Type I diabetes by providing a cell-based means to mimic the normal physiological response to glucose. While promising, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological responses to the transplant, primarily instigated by cell surface proteins and antigens. While polymeric encapsulation has shown strong potential in murine models, clinical translational of this approach is poor. Insufficient clinical efficacy is attributed to the significant nutritional deficiencies imposed by standard microencapsulation, as well as immunorecognition and subsequent innate and adaptive responses to the foreign graft. In this proposal, we seek to shift this standard encapsulation paradigm by incorporating both innovative nano-scale polymeric coatings and novel functionalization strategies to distinctly modulate immune responses. With evidence that encapsulation can be highly synergistic with immunomodulatory agents, we seek to generate bioactive, immunomodulatory coatings through bio-orthogonal chemistry that serves to not only to mask donor cell surface proteins but also direct the local immune response towards a tolerogenic phenotype through the generation of a supportive milieu. We hypothesize that the polymer grafting of islets to express functional handles for the conjugation of immunomodulatory agents and/or nanoparticles will enhance islet engraftment and functional duration by both masking host recognition of surface antigens and generating a local immunoregulatory environment to support the long-term survival of the transplanted islets. To test this hypothesis, immunomodulatory agents will be bio- orthogonally tethered to nano-scale coatings on the islet surface and screened for their capacity to skew host immune responses towards tolerogenic phenotypes in vitro and in diabetic murine models (Aim 1). Further, to generate a supportive graft microenvironment and protective coating, reactive oxygen species (ROS) nanoparticles will be into nano-scale coatings (Aim 2). Using innovative in vitro screening platforms, ideal immunomodulatory coatings will be selected, with subsequent validation in diabetic murine models. The design of effective strategies to combine stable nano-scale coatings with local immunomoduation could significantly improve the efficacy and long-term stability of islet transplants in the absence of chronic, systemic immunosuppression.
The development of treatment options for insulin-dependent diabetics with islet cells, which provide physiological regulation of glucose, could result in dramatic improvements in quality of life, as well as a substantial decrease in disease management complications. Herein, we seek to develop a novel encapsulation approach that serves to minimize or eliminate the need for anti-rejection therapy following an islet cell transplant, which should significantly enhance treatment options for insulin-dependent diabetics. We believe these studies are highly relevant to the mission of the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) and are designed to result in a significant impact on public health.
