Type 1 diabetes (T1D), an autoimmune disorder prevalent in 1.6 million Americans, is growing rapidly with 64,000 yearly diagnoses and costing the U.S. $16 billion annually. Pancreatic islet transplantation has shown promise in treating T1D, however, immune rejection and continuous use of immunosuppression to control rejection limit clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and has significant adverse effects on graft recipients as ~50% of recipients maintain insulin independence at five years. Therefore, there is a significant need to prevent graft rejection without an immunosuppressive regimen. Uncontrolled expansion of islet-reactive T effector (Teff) cells in pre-diabetics reaches a point where it cannot be contained by protective T regulatory (Treg) cells. This further complicates transplantation of allogeneic islets due to rejection by both alloreactive and autoreactive Teff cells. To tilt the balance in favor of Treg cells, approaches have targeted Teff or Treg cells individually for modulation with limited success. The objective of this project is to target Treg and Teff cells simultaneously by engineering a novel biomaterial strategy to achieve localized immunotolerance to islet allografts. Since Teffs activated by antigens express Fas receptor, becoming sensitive to FasL-mediated apoptosis, a chimeric form of the Fas agonist, FasL, and a streptavidin core has been engineered (SA-FasL), to be presented on biotinylated biomaterials and induce Teff apoptosis. Since IL-2R signaling preferentially sensitizes Teff cells to Fas-induced cell death while promoting Treg expansion, a recombinant IL-2R agonist has been engineered, IL-2D, to be presented alongside SA-FasL. The central hypothesis is that controlled delivery of SA-FasL/IL-2D via engineered biomaterials will increase the number of antigen-specific Tregs and decrease the number of antigen-specific Teffs, creating an immune-tolerant microenvironment at the graft site that prolongs islet graft survival in the absence of systemic immunosuppression. Preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application, which will be accomplished across two specific aims: 1) Engineer a synthetic hydrogel platform that delivers SA-FasL and IL-2D to induce immune tolerance to transplanted islets. 2) Evaluate the efficacy of the IL-2D/SA-FasL hydrogel to achieve sustained graft survival in a spontaneously diabetic NOD mouse model. Expected outcomes include local immune tolerance in the absence of immunosuppression by the controlled release of IL-2D/SA-FasL and a greater understanding of the mechanisms responsible for the induction immune privilege. If accepted, the applicant will also undergo training aimed at developing 1) technical and analytical research skills, 2) oral and written communication skills, 3) strong leadership traits, and 4) entrepreneurial expertise. Direct mentoring from Dr. Garca, the Georgia Tech BME Ph.D. curriculum, and participation in scientific meetings will facilitate this training.
Type 1 diabetes (T1D) is a chronic disease that arises from the autoimmune destruction of insulin-producing ? cells. Despite advances in cell therapies aimed at replacing lost ? cells in type 1 diabetics, the need for lifelong immunosuppression to prevent transplant rejection creates complications that have limited the widespread use of cell therapies to cure T1D. The objective of this project is to engineer a biomaterials-mediated strategy to create an immune privileged microenvironment that prevents rejection of transplanted cells in the absence of immunosuppression.
