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Principal Investigator: Farhan Qureshi
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $28,079
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Address><Affect><After Care><After-Treatment><Aftercare><American><Apoptosis><Apoptosis Pathway><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Autoregulation><B9 endocrine pancreas><Beta Cell><Biology><Biomedical Research><Blood><Blood Glucose><Blood Reticuloendothelial System><Blood Sugar><Body Tissues><Brittle Diabetes Mellitus><CD25><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Count><Cell Death><Cell Function><Cell Interaction><Cell Number><Cell Physiology><Cell Process><Cell Signaling><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chimera Protein><Chimeric Proteins><Ciclosporin><Clinical><Clinical Research><Clinical Study><Clinical Trials><Co-Stimulator><Costimulator><CsA><Cyclosporin A><Cyclosporine><Cyclosporine A><Data><Diabetes Mellitus><Diagnosis><Disease><Disease Progression><Disorder><Dose><Dysfunction><Endocrine><Endocrine Pancreas><Endoplasmic Reticulum><Environment><Epidermal Thymocyte Activating Factor><Ergastoplasm><Fasting><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Foundations><Functional disorder><Fusion Protein><Goals><Half-Life><Health><Homeostasis><Humulin R><IDDM><IL-2><IL2 Protein><IL2R><IL2RA><IL2RA gene><Immune><Immune Tolerance><Immune infiltrates><Immune mediated therapy><Immunes><Immunologic Tolerance><Immunologically Directed Therapy><Immunomodulation><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Immunotherapy><Impairment><In Situ><In Vitro><Inbred NOD Mice><Individual><Infiltration><Inflammatory><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investments><Islands of Langerhans><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Knowledge><Lymphatic cell><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocytic><Mediating><Mitogenic Factor><Modeling><Monitor><NIH><NOD Mouse><NOR Mouse><National Institutes of Health><Nesidioblasts><Non obese><Non-Obese Diabetes Resistant mouse><Non-Obese Diabetic Mice><Nonobese><Nonobese Diabetes Resistant mouse><Nonobese Diabetic Mouse><Novolin R><Pancreas><Pancreatic><Pancreatic Islets><Pars endocrina pancreatis><Pathogenesis><Patients><Pattern><Phase 1/2 Clinical Trial><Phase I/II Clinical Trial><Physiological Homeostasis><Physiopathology><Population><Pre-Clinical Model><Preclinical Models><Preparation><Prevention><Programmed Cell Death><Proliferating><Recombinant Interleukin-2><Regular Insulin><Regulatory T-Lymphocyte><Sandimmun><SangCya><Science><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Staining method><Stains><Strategic Planning><Stress><Subcellular Process><Sudden-Onset Diabetes Mellitus><T cell growth factor><T-Cell Growth Factor><T-Cell Stimulating Factor><T1 DM><T1 diabetes><T1D><T1DM><TCGFR><Teff cell><Testing><Thymocyte Stimulating Factor><Time><Tissues><Treatment Efficacy><Treg><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><United States National Institutes of Health><Work><analog><autoimmune attack><autoimmune condition><autoimmune destruction><autoimmune disorder><autoimmune pathogenesis><autoimmunity disease><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biological adaptation to stress><biological signal transduction><blood glucose regulation><cytokine><diabetes><diabetes pathogenesis><diabetic><effector T cell><efficacy trial><fasted><fasts><functional restoration><glucose control><glucose homeostasis><glucose regulation><glucose tolerance><immune cell infiltrate><immune modulation><immune regulation><immune suppressive 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pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pathophysiology><post treatment><pre-clinical study><pre-clinical trial><preclinical study><preclinical trial><preparations><preservation><prevent><preventing><reaction; crisis><regulatory T-cells><response><restoration><restore function><restore functionality><restore lost function><sandimmune><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><stress response><stress; reaction><therapeutic efficacy><therapy efficacy><type I diabetes><type one diabetes><β-cell><β-cells><βCell>