Promoting Tolerance in Myogenic Diseases 2705

Description A common concern in monogenic disorders, particularly in gene therapy, is the lack of immunological tolerance to the protein normally produced by the affected gene. Peripheral mechanisms of immune tolerance suppress self-reactive T cells that escape central tolerance, with regulatory T cells (Tregs) playing a central role in this process. Duchenne muscular dystrophy is a monogenic disease in which the DMD gene is mutated, resulting in the absence of dystrophin protein. Studies have shown that a substantial fraction of these patients harbor dystrophin-specific T cells, suggesting a lack of central tolerance. However, the role of these T cells and whether they are actively suppressed by Tregs is not well understood. Here, we report the development of a DMD mouse model to study dystrophin immunity. The induction of dystrophin-specific T cells was confirmed by IFNγ+CD44+ CD8+ or CD4+ T cells in recall antigen assays. Depletion studies revealed that Tregs limit the induction of dystrophin-specific T cells. Furthermore, expanding Tregs using a single-agent human interleukin-2 (IL-2)/antibody fusion protein (immunocytokine, IC) effectively suppressed dystrophin-specific T cells. A fusion protein linking a miniaturized version of the IC (miniIC) to an anti-alpha-dystroglycan (α-DAG) antibody was engineered to achieve muscle-specific delivery. Future studies will focus on evaluating the efficacy of the DAG-targeted miniIC in suppressing dystrophin-specific T cells in vivo.