Friday, April 19, 2024
4/19/2024
Project Summary Type 1 diabetes (T1D) is a devastating autoimmune disease affecting over 1.25 million Americans that currently has no cure. Therapies which target autoimmunity in T1D have shifted away from broadly immunosuppressive agents such as cyclosporine, and now focus on enhancing immune tolerance. Low-doses of interleukin-2 (IL-2) have been shown in pre-clinical and clinical trials to induce proliferation of regulatory Tcells (Tregs) which promote immune tolerance and prevent autoimmune destruction of the insulin producing beta cell. Recently, it has been shown in preclinical models that an IL-2/CD25 fusion protein induces greater proliferation of Tregs and has a longer half-life than traditional recombinant IL-2. Studies on IL-2 and its analogues have focused on mechanisms of immune tolerance and how it prevents loss of beta cell mass. Recent clinical findings demonstrate that insulin secretion is impaired at least five years before diagnosis, while beta cell mass is still preserved, suggesting that beta cell dysfunction, in addition to loss of beta cell mass, is critically important to the pathogenesis of T1D. It is currently unknown how IL-2/CD25 therapy affects beta cell dysfunction. This represents a critical gap in knowledge that must be addressed. Preliminary data shows that IL-2/CD25 induces changes in the local immune infiltrate, increasing the proportion of Tregs and decreasing the proportion of effector T cells (Teffs) at the islets. In vitro studies have shown that pro-inflammatory cytokines are released by infiltrating Teffs and cause beta cell dysfunction via stress on the endoplasmic reticulum (ER). Therefore, I hypothesize that IL-2/CD25 works to delay T1D progression by preventing cytokine-mediated beta cell dysfunction, not just by averting cell death. I plan to test this hypothesis in the following specific aims: 1) Determine how IL-2/CD25 treatment preserves islet function and glucose homeostasis, 2) Determine how IL- 2/CD25 treatment preserves islet tissue homeostasis. Under the first aim, I will use a novel approach using living pancreas slices to analyze changes in insulin secretion and intracellular Ca2+ dynamics after IL-2/CD25 treatment. Under the second aim, I will identify the specific mechanisms involved in restoring islet homeostasis after IL-2/CD25 therapy by using immunostaining and single-cell RNA sequencing for markers of stress, proliferation, and dedifferentiation. My proposed study is significant because it will yield new information about how changes in local immune infiltration mediated by IL-2/CD25 affect islet biology. This contribution is significant because it will provide fundamental knowledge that will complete and revise models about immunotherapies for T1D. This study supports the strategic plans of the National Institutes of Health which include advancing opportunities in biomedical research by investing in fundamental science and developing treatments/cures for disease.
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