PDL1-based rAAV-mediated gene therapy for mouse T1D

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DESCRIPTION (provided by applicant): The PD-1/PDL-1 signaling has been shown to be a crucial regulator for activated T cell function. Engagement of the PD-1 by PD-L1 down-regulates effector T cell proliferation and cytokine production, and induces T cell cycle arrest and apoptosis or promotes IL-10-producing regulatory T cell responses. However, little is known the role of PDL1 -related signaling in T cell responses to (3-cell antigens and the T1D process. Recent studies have shown that NOD mice are deficient in expression of PDL1 on APCs, islet-specific transgenic expression of PDL1 significantly reduced insulitis and prevented diabetes in NOD mice, and treatment with blockade for PD-1/PDL1 signaling rapidly precipitated diabetes onset in young NOD mice. Our preliminary studies showed that agonistic PDL1-lg inhibited spontaneous Th1 response to p-cell antigens, arrested diabetogenic T cell cycling in vitro, and treatment with PDL1-lg retarded the onset of adoptively transferred T1D in vivo. In addition, transplantation with syngenic islets transduced by recombinant adeno-associated virus (rAAV)-PDLI-lg, but not rAAV-lg, prolonged islet-graft survival in diabetic NOD mice and treatment of 6 weeks old NOD mice with rAAV-PDL1-lg induced stable expression of PDL1-lg, inhibited disease progression, associated with inhibition of spontaneous T cell autoimmunity. Hence, we hypothesize that treatment with rAAV-PDL1-lg to induce PDL1-lg stable expression may inactivate effector T cells and/or induce regulatory T cell responses, inhibiting disease progression at advanced pre-T1D and reverse T1D in NOD mice. We choose to use AAV as the vector to deliver PDL1-lg or control Ig genes to NOD mice because AAV is a non-pathogenic virus and has little immunogenicity, making it attractive for clinical applications. AAV can effectively infect broad types of cells, leading to a long-term expression of target genes. In this proposal, we will examine the effect of treatment with rAAV- PDL1-lg at the late stage of autoimmune process on disease progression and on reversal of newly diabetes in NOD mice and determine the mechanism(s) underlying the action of PDL1-related signaling on the process of T cell autoimmunity in NOD mice. Our studies will address fundamental questions concerning the regulatory function of PD-1/PDL1 signaling on autoimmune T cell responses. Our findings may provide the basis for novel immunotherapies for the inhibition/reversal of T1D in human. Layperson's abstract: We will center on examining the therapeutic effect of an engineered inhibitor for T cell autoimmunity on inhibition/reversal of type 1 diabetes in mouse model. Our findings may provide a basis for the design of specific immunotherapies for T1D patients.