T1D Tolerance Induction with Natural Treg Epitopes

使用天然 Treg 表位诱导 T1D 耐受

基本信息

批准号：
7480885
负责人：
Anne Searls DeGroot
金额：
$ 49.36万
依托单位：
EPIVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7480885
关键词：
Adolescent Alleles Antigens Autoimmune Diseases Autologous Beta Cell Binding Biological Assay CD8B1 gene Cells Characteristics Chimeric Proteins Class Clinical Development Diabetes Mellitus Disease Progression Doctor of Medicine Doctor of Philosophy Dose Enzyme-Linked Immunosorbent Assay Epitopes Exhibits Flow Cytometry Glucose Intolerance Goals HLA Antigens Histocompatibility Antigens Class II Human Hypersensitivity Immune Immune response Immunity Immunoglobulins Immunologist Immunophenotyping In Vitro Inbred NOD Mice Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Lead Length Lymphocyte Maryland Measures Modeling Mus Organ Outcome Pathology Patients Peripheral Blood Mononuclear Cell Phase Phenotype Prevention Proteins Protocols documentation Public Health Publications Publishing Research Research Activity Risk Route SCID Mice Small Business Funding Mechanisms Small Business Innovation Research Grant Structure of beta Cell of islet System T-Lymphocyte T-Lymphocyte Epitopes TNFRSF10A gene Therapeutic Intervention Toxic effect Transgenic Mice Week chemokine commercialization contextual factors cytokine design diabetic early onset glucose tolerance immunogenic in vivo mouse model non-diabetic preproinsulin prevent programs pyroglyphid research and development research study response therapeutic protein type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Type 1 (juvenile) diabetes is an organ-specific autoimmune disease resulting from destruction of insulinproducing pancreatic beta-cells. In non-diabetics, islet cell antigen-specific T cells are either deleted in thymic development or are converted to T regulatory cells that actively suppress effector responses to islet cell antigens. In juvenile diabetics and in the NOD mouse model of juvenile diabetes, these tolerance mechanisms are missing. In their absence, islet cell antigens are presented by human leukocyte antigen (HLA) class I and II molecules and are recognized by CD8(+) and CD4(+) auto-reactive T cells. Destruction of islet cells by these auto-reactive cells eventually leads to glucose intolerance. Modulation of auto-immune responses to autologous epitopes by induction of antigen-specific tolerance may prevent ongoing beta-cell destruction. EpiVax, Inc. has identified a set of natural T regulatory epitopes that induce tolerance to immunogenic proteins. Preliminary studies demonstrate that these "Tregitopes" specifically induce natural Tregs and, when coadministered with an antigen, lead to expansion of antigen-specific regulatory T cells. Initial studies have demonstrated tolerance induction in the context of dust-mite allergy. The goal of this Phase I SBIR application is to evaluate whether immune response to islet cell antigens can be redirected by administration of Tregitopes in conjunction with T1D antigens, leading to "antigen-specific adaptive tolerance induction" (T1D ASATI) in a murine model of T1D. The outcome of T1D ASATI will be measured in terms of regulatory T cell responses to preproinsulin (PPI) T-cell epitopes in vivo and in vitro. In the context of this application we will: (1) Assess whether Tregitopes suppress the PPI-specific response ex vivo using PBMC from recent-onset type 1 diabetics, (2) Measure Tregitope-induced modulation of T1D pathology and PPI-specific immune responses in NOD mice and (3) Elucidate the mechanism of Tregitopeinduced PPI ASATI in DR4 transgenic mice. If successful, this research and development program will lead to a clinical approach that will generate or restore tolerance in juvenile diabetics. PUBLIC HEALTH RELEVANCE: This research will investigate an immune treatment that may slow the progression of Type 1 (juvenile) diabetes.

描述（由申请人提供）：1型（少年）糖尿病是一种特定器官特异性的自身免疫性疾病，导致胰岛素生产的胰腺β细胞破坏。在非糖尿病患者中，胰岛细胞抗原特异性T细胞要么在胸腺发育中被删除，要么转化为T调节细胞，从而积极抑制效应子对胰岛细胞抗原的反应。在青少年糖尿病患者和青少年糖尿病小鼠模型中，这些耐受性机制缺失。在缺乏的情况下，胰岛细胞抗原由人白细胞抗原（HLA）I类和II类分子表示，并由CD8（+）和CD4（+）自动反应性T细胞识别。这些自动反应性细胞破坏胰岛细胞最终导致葡萄糖不耐症。通过诱导抗原特异性耐受性来调节自动免疫对自体表位的反应可能会阻止持续的β细胞破坏。 ePivax，Inc。已确定一组诱导免疫原性蛋白质耐受性的天然T调节表位。初步研究表明，这些“ tregitopes”专门诱导天然Treg，并与抗原共同施加时会导致抗原特异性调节性T细胞的扩展。初步研究表明，在尘埃过敏的背景下，耐受性诱导。该阶段I SBIR应用的目的是评估对胰岛细胞抗原的免疫反应是否可以通过与T1D抗原结合使用，将Tregitopes施用重定向，从而导致“ T1D的小鼠模型中”“抗原特异性适应性耐受诱导”（T1D ASATI）。 T1D ASATI的结果将以调节性T细胞对前硫蛋白（PPI）T细胞的反应在体内和体外进行测量。在此应用程序的背景下，我们将：（1）评估Tregitopes是否使用最近发作1型糖尿病患者的PBMC抑制了PPI特异性反应，（2）测量T1D病理学的调节和PPI特异性反应的NOD小鼠和（3）Elucigy the tregitope integenigy tregitoge integenigiant tregitoge int tregitoge Indegitigy tregitoge interigy tregitoge。如果成功，该研究与发展计划将导致一种临床方法，该方法将产生或恢复少年糖尿病患者的耐受性。公共卫生相关性：这项研究将调查一种免疫治疗，可能会减慢1型（少年）糖尿病的进展。