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A Novel Therapy for Restricted Induction of Tolerance to Treat Diabetes Mellitus

限制性诱导耐受治疗糖尿病的新疗法

基本信息

批准号：
8448933
负责人：
Kanneganti Murthy
金额：
$ 26.99万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-19 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8448933
关键词：
Acute Adoptive Transfer Age Animal Model Antigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Behavior Binding Sites Biochemical Blood Glucose Blood Vessels Body Weight CD4 Positive T Lymphocytes CXC chemokine receptor 3 CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Calcineurin inhibitor Cell Therapy Cells Cellular Immunity Chimeric Proteins Clinical Colitis Complications of Diabetes Mellitus Data Dependence Diabetes Mellitus Diabetic mouse Disease Disease Progression Disease remission Dose Enzyme-Linked Immunosorbent Assay Equilibrium Experimental Autoimmune Encephalomyelitis Experimental Models Female Functional disorder Grant Harvest Histologic Hyperglycemia IL2RA gene IgG1 Immune Immune Tolerance Immunity Immunologics Immunomodulators Immunosuppressive Agents In Vitro Inbred NOD Mice Infiltration Inflammatory Response Injury Insulin Insulin-Dependent Diabetes Mellitus Interleukin-10 Intraperitoneal Injections Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Kidney Ligand Binding Location Lung Lymphocyte Maintenance Metabolic Modeling Monitor Mus Neurologic Onset of illness Organ Pancreas Pathway interactions Peripheral Pharmaceutical Preparations Phase Phosphorylation Physiologic pulse Plasma Property Recovery Regulatory T-Lymphocyte Relative (related person)Research Rodent Model STAT3 gene Scientific Advances and Accomplishments Signal Transduction Sirolimus Small Business Innovation Research Grant Spleen Steroids T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Therapeutic Time Tissues Transfusion Translating United States National Institutes of Health Universities cell injury chemokine clinically relevant cytokine diabetic functional outcomes human FRAP1 protein in vivo innovation islet liver injury neutrophil next generation novel public health relevance receptor research study response transcription factor type I diabetic

项目摘要

DESCRIPTION (provided by applicant): We are developing a novel immunomodulatory approach to arrest pancreatic islet injury and restore specific immune tolerance in new-onset Type 1 diabetes mellitus (T1D). Damage of pancreatic islets in T1D may result from excess pathogenic Th1/Th17 cells and deficient tolerance-inducing antigen (Ag)-specific Treg (FOXp3+CD25+) and Tr1 CD4+ cells (FOXp3-CD25- IL-10high). Lacking suitable levels of Tr1 cells, pathogenic activated Th1/Th17 cells are unopposed, resulting in islet cell damage and destruction. Our approach, which redirects the polarization of autoimmune-activated Th1/Th17 cells towards tolerance-inducing Tr1 cells, is grounded in research showing that the transfusion of ex vivo produced Ag-specific Tr1 cells is protective in experimental models of autoimmunity, such as experimental T1D and islet cell transplantation. Ex vivo repolarization of Th1 cells, however, is cumbersome and expensive. In our in vivo approach, we parentally administer CXCL11 ("mR-412"), a CXCR3-binding ligand that we have recently identified as a counter-regulatory chemokine. Therapy with a long-acting Fc fusion protein of CXCL11 ("mR-411") profoundly suppresses murine experimental allergic encephalomyelitis (EAE), even when initiated after disease onset. Moreover, Ag-specific effector Th1 cells isolated from EAE donors treated in vivo with mR-411 redirect their polarization into Tr1 cells and suppress EAE in adoptive transfer experiments. In contrast to pan-suppressive immunomodulators, mR-411 induces tolerance that is Ag-specific for the active disease yet preserves generalized immunity to previously encountered antigens. We now seek to extend these observations and establish proof-of-concept that mR-412 establishes immune tolerance of islets in a murine model of T1D. Specific Aim #1: Establish the potency, dose-dependence, and durability of mR-412 rescue therapy of well- established diabetes mellitus in a spontaneous murine T1D model. mR-412 (0, 4, 40 ?g/kg IP 2 X per week) will be dosed for 18 weeks to female diabetic NOD mice beginning at 180 days of age, a time point characterized by established hyperglycemia. Mice will be terminated either directly at the cessation of mR-412 therapy (acute group) or 12 weeks thereafter (recovery group). We will examine pancreases for histologic and immunohistochemical evidence of islet injury and determine insulin content. Spleen and pancreases will be examined for: 1) intracellular cytokine expression in lymphocytes, and 2) immunohistochemical identification of T cell subset infiltration and the phosphorylation of T-bet and STAT3. Plasma concentrations of mR-412 will be determined by ELISA and compared to functional outcomes. We expect that mR-412 will restore normoglycemia until the conclusion of the recovery period. Supportive data will include dose-dependent demonstration that mR-412 produces favorable biochemical and immunologic effects on islets harvested at the time of sacrifice, including the maintenance of islet insulin content, the blockade of T-cell infiltration nd T-bet phosphorylation, and STAT3 phosphorylation.

描述（由申请人提供）：我们正在开发一种新的免疫调节方法，以阻止新发1型糖尿病（T1 D）的胰岛损伤并恢复特异性免疫耐受。T1 D患者的胰岛损伤可能是由于Th 1/Th 17细胞过多和抗原特异性Treg（FOXp 3 + CD 25+）和Tr 1 CD 4+细胞（FOXp 3-CD 25- IL-10 high）缺乏所致。缺乏合适水平的Tr 1细胞，致病性活化的Th 1/Th 17细胞不受抵抗，导致胰岛细胞损伤和破坏。我们的方法，重新定向的自身免疫激活的Th 1/Th 17细胞对耐受诱导Tr 1细胞的极化，是基于研究表明，输血离体产生的Ag特异性Tr 1细胞是保护性的自身免疫实验模型，如实验T1 D和胰岛细胞移植。然而，Th 1细胞的离体复极化是麻烦且昂贵的。在我们的体内方法中，我们肠胃外施用CXCL 11（“mR-412”），CXCR 3结合配体，我们最近鉴定为反调节趋化因子。用CXCL 11的长效Fc融合蛋白（“mR-411”）的治疗深刻地抑制鼠实验性过敏性脑脊髓炎（EAE），即使在疾病发作后开始。此外，从用mR-411体内处理的EAE供体中分离的Ag特异性效应Th 1细胞将其极化重定向为Tr 1细胞，并在过继转移实验中抑制EAE。与泛抑制性免疫调节剂相反，mR-411诱导对活动性疾病具有Ag特异性的耐受性，但保留对先前遇到的抗原的全身免疫。我们现在试图扩展这些观察结果，并建立概念验证，即mR-412在T1 D小鼠模型中建立胰岛的免疫耐受。具体目标1：在自发性小鼠T1 D模型中确定mR-412补救治疗对已确诊糖尿病的效力、剂量依赖性和持久性。mR-412（0、4、40？g/kg IP每周2次）给药18周至180日龄的雌性糖尿病NOD小鼠，该时间点的特征在于确定的高血糖症。小鼠将在mR-412治疗停止时直接处死（急性组）或12周后处死（恢复组）。我们将检查胰腺的组织学和免疫组化证据胰岛损伤和确定胰岛素含量。将检查脾和胰腺的：1）淋巴细胞中的细胞内细胞因子表达，和2）T细胞亚群浸润和T-bet和STAT 3磷酸化的免疫组织化学鉴定。将通过ELISA测定mR-412的血浆浓度，并与功能结果进行比较。我们预计mR-412将恢复正常，直至恢复期结束。支持性数据将包括剂量依赖性证明，即mR-412对处死时收获的胰岛产生有利的生物化学和免疫学作用，包括维持胰岛胰岛素含量、阻断T细胞浸润和T-bet磷酸化以及STAT 3磷酸化。