There is a critical need to develop antigen-specific therapies for the treatment of type 1 diabetes (T1D) to avoid the major side-effects of broad-based immunosuppressive therapies. Our laboratory has developed a treatment strategy for autoimmune disorders in which the pathogenic autoreactive T cells are safely and specifically inactivated while leaving the remaining immune system unperturbed, i.e. the induction antigen-specific immunologic tolerance. Our approach has been to chemically cross-link autoantigenic proteins/peptides to syngeneic splenic leukocytes using a chemical cross-linking agent, ethylene-carbodiimide (ECDI). We have demonstrated that intravenous injection of antigen-coupled splenocytes (Ag-SP) is a highly efficacious method for the induction of tolerance for both the prevention and treatment of a variety of immune-mediated disorders including experimental autoimmune encephalomyelitis (EAE), the animal model for MS, T1D in the NOD mouse, and transplant rejection. This protocol was recently successfully tested in a Phase I clinical trial in MS patients demonstrating the safety and efficacy of tolerance induced by ECDI-fixed autologous PBLs (Ag-PBL) coupled with a myelin peptide cocktail in specifically regulating myelin-reactive autoreactive T cell responses. Although this tolerance protocol will hopefully prove to be an effective therapy for treatment of human autoimmune diseases, the cost and complexity of the cell manufacturing process is a detriment to its widespread clinical use. To overcome this limitation, we have recently developed a new generation protocol in which tolerance can be effectively induced by the intravenous injection of antigen encapsulated in inert biodegradable nanoparticles composed of the FDA-approved biopolymer poly(lactide-co-glycolide) (PLG). Our preliminary studies show that treatment with PLG nanoparticles encapsulating diabetic antigens is effective for prevention of disease initiation in NOD mice and for specific regulation of activated β cell antigen-specific T cells in a cell transfer model of T1D by activating specific regulatory T cells. The experiments proposed will advance these preliminary studies providing critical information required to support the clinical translation of this therapy. Three specific aims will examine the breadth of autoantigenic epitopes that can be targeted using protein/peptide Ag-encapsulated PLG particles; the specificity of the induced regulation; the differential ability to induce tolerance in naïve vs. activated diabetogenic CD4+ and CD8+ T cells; and optimization of more clinically feasible delivery routes for tolerance induction. Knowledge gained through these studies will help to advance the clinical translation of this novel antigen-specific therapy for the treatment of T1D and other autoimmune diseases.
|Effective start/end date||11/1/14 → 11/30/17|
- JDRF International (2-SRA-2014-279-Q-R)