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Targeted delivery of immunomodulatory biologics for induction of immune privilege to allogeneic pancreatic islet grafts

靶向递送免疫调节生物制剂以诱导同种异体胰岛移植物的免疫特权

基本信息

批准号：
10227259
负责人：
Andres J Garcia
金额：
$ 42.1万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-12 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227259
关键词：
Acute Adverse effects Affect Agonist Allogenic Antigens Apoptosis Apoptotic Autoantigens Autoimmune Diseases Beta Cell Binding Biocompatible Materials Biological Biological Process Biological Response Modifiers C57BL/6 Mouse CD8B1 gene CD95 Antigens Cell Death Cell membrane Chemicals Chronic Clinical Clinical Treatment Clinical Trials Cloning Complex Data Development Engineering Equilibrium Eragrostis FOXP3 gene Failure Formulation Frequencies Generations Goals Graft Rejection Graft Survival Homeostasis Human Hydrogels Hyperglycemia Hypoglycemia IL2 gene IL2RA gene Immune Immune response Immunosuppression Immunosuppressive Agents Inbred BALB C Mice Inbred NOD Mice Individual Innate Immune Response Insulin Insulin-Dependent Diabetes Mellitus Interleukin-2 Islets of Langerhans Islets of Langerhans Transplantation Lead Lesion Life Mediating Membrane Memory Metabolic Control Modeling Outcome Pathogenicity Pathway interactions Patients Peripheral Physiological Play Polyethylene Glycols Population Pre-Clinical Model Prevention Protocols Protocols documentation Quality of life Rattus Recurrence Regulatory T-Lymphocyte Research Rodent Role Signal Pathway Signal Transduction Skin Streptavidin Surface T memory cell T-Lymphocyte Testing Therapeutic Time Translations Treatment Protocols Tumor Necrosis Factor Ligand Superfamily Member 6 Work alternative treatment autoreactivity base cell type chronic autoimmune disease controlled release design diabetic effective therapy effector T cell efficacy testing extracellular graft function humanized mouse immunoregulation immunosuppressed improved innovation islet islet allograft mouse model negative affect nonhuman primate novel novel strategies particle prevent receptor response standard of care success synergism targeted delivery therapeutic target translation to humans

项目摘要

PROJECT SUMMARY Type 1 diabetes (T1D) is a chronic autoimmune disorder that affects ~1% of population worldwide. Exogenous insulin treatment is the standard of care for T1D, but often negatively affects the quality of life and is ineffective in preventing recurrent hyperglycemia episodes and chronic complications. Recent studies show that human islet allografts can restore long-term normoglycemia and insulin independence, protect from severe hypoglycemia, and slow progression of microvascular lesions in immunosuppressed T1D patients. However, immune rejection and continuous use of immunosuppression to control rejection are two major limitations of clinical islet transplantation. Standard immunosuppression is ineffective in achieving long-term graft survival and also has significant adverse effects on the graft and graft recipients. Therefore, the development of novel approaches to prevent rejection of islet grafts without chronic immunosuppression is a significant goal. Allogeneic islets are subject to rejection by both alloreactive and autoreactive T effector (Teff) cells. An imbalance in the frequency of pathogenic Teff and protective T regulatory (Treg) cells is the underlying cause of T1D and allogeneic islet graft rejection. Restoring the physiological Teff and Treg balance has significant therapeutic potential. Approaches attempting to tilt the balance in favor of Treg cells have so far targeted either Teff or Treg cells individually for modulation with limited success. The primary goal of this application is to target both cell types simultaneously for modulation for an outcome in favor of Treg cell expansion. This will be achieved using innovative polyethylene glycol hydrogel particle platforms for graft-targeted delivery and controlled presentation of two novel biologics serving as agonists of Fas and IL-2R receptors. Teff cells activated by antigens express Fas receptor and become sensitive to FasL-mediated apoptosis. IL-2R signaling preferentially sensitizes Teff cells to Fas-induced apoptosis and is also required for Treg cells (CD4+CD25+FoxP3+) generation, expansion, and survival. Therefore, we hypothesize that the combined use of agonists of Fas and IL-2R will preferentially eliminate Teff cells and generate/expand Treg cells within the graft microenvironment, resulting in induced-immune privilege and sustained survival and function of islet allograft in the absence of any immunosuppression. A set of preliminary data support this hypothesis and provide strong scientific premise and feasibility for this application. This concept will be tested in three different allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to- C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice, and human islets into humanized mice. These models will generate critical data relevant to the human setting. Furthermore, proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials for the treatment of type 1 diabetes.

项目总结