Project Summary
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.
García, the Georgia Tech BME Ph.D. curriculum, and participation in scientific meetings will facilitate this training.