Objective
We hypothesize that nanodiscs formulated with autoantigens derived from islet antigens will provide a new strategy for modulating immune microenvironment of pancreas, leading to immune tolerance against type 1 diabetes (T1D). Here, we propose to examine the efficacy of our nanodiscs as both a preventative treatment and a potential cure for type 1 diabetes in mouse models and with human cells. and identify our lead candidate for treatment of T1D by screening nanodisc samples using human T1D patients.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease that affects approximately 1 in 300 people by the age of 18 in the US. For managing symptoms of T1D, daily insulin replacement therapy is required and costly but it does not address the underlying autoimmune mechanisms. T1D results from immune-mediated destruction of the insulin-producing β-cells in the pancreas. Self-reactive CD4 and CD8 T cells are central pathogenic drivers. On the other hand, regulatory T cells (Tregs) restrain autoimmunity and maintain immune tolerance through multiple mechanisms, including production of IL-10 and TGF-β, mitigation of inflammatory mediators, sequestration of IL-2 and generation of other regulatory cell populations such as regulatory B cells. In T1D patients, impaired regulatory T cell function contributes to disease susceptibility in addition to genetics and environment. Targeting Tregs holds great promise in correcting the aberrant T cell activities and preventing the progression of T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease that affects 1 in 300 people by the age of 18 in the US. T1D is characterized by acute onset of hyperglycemia resulting from immune-mediated destruction of the insulin-producing β-cells in the pancreas. While self-reactive CD4 and CD8 T cells are central pathogenic drivers, regulatory T cells (Tregs) have been shown to restrain autoimmunity and maintain immune tolerance through multiple mechanisms. In T1D patients, impaired Treg function have been shown to contribute to disease susceptibility. Thus, induction of Tregs therefore holds great promise in correcting the aberrant autoreactive T cell activities and preventing the progression of T1D. However, it remains unknown how to induce Tregs in a safe and effective manner for the potential treatment of T1D. Here, we propose to develop a nanoparticle system that can promote antigen-specific immune tolerance. Our preliminary data generated in a murine model of multiple sclerosis has shown the promise of our nanotechnology, and here we propose to further develop our nanotechnology for induction of Tregs against autoreactive antigens in T1D. The proposed research will provide a new strategy for modulating immune microenvironment of pancreas and an avenue for immune tolerance against T1D. It will generate new fundamental knowledge in drug development, address current technical limitations in therapies against autoimmune diseases, and lead to new strategies to achieve immune tolerance.
Anticipated Outcome
We anticipate that treatment of NOD mice with our nanodisc vaccine will induce antigen-specific Tregs and protect them from disease initiation in a preventive setting. In addition, we anticipate that nanodisc vaccine will reverse new -onset diabetes in a therapeutic setting. render acutely diabetic mice normoglycemic. We will also identify a lead candidate T1D antigen-nanodisc for future clinical translation. Overall, our studies may lead to a novel approach for inducing antigen-specific immune tolerance and provide a new pathway for immune intervention approach against T1D.
Relevance to T1D
Here, we will develop a new nanoparticle platform that can induce antigen-specific immune tolerance, correct autoreactive T cells, and precisely modulate the autoimmune processes that drives T1D. The proposed research will provide a new strategy for modulating immune microenvironment of pancreas and may lead to a new avenue for immune tolerance against T1D.