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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来阻止新发1型糖尿病（T1D）的胰岛损伤和恢复特异性免疫耐受。T1D患者胰岛的损伤可能是由于致病性Th1/Th17细胞过多和耐受诱导抗原（Ag）特异性Treg （FOXp3+CD25+）和Tr1 CD4+细胞（FOXp3-CD25- IL-10high）缺乏所致。由于缺乏适当水平的Tr1细胞，致病性激活的Th1/Th17细胞无法对抗，导致胰岛细胞损伤和破坏。我们的方法，将自身免疫激活的Th1/Th17细胞的极化重新定向到耐受诱导的Tr1细胞，是基于研究表明，在自身免疫的实验模型中，如实验性T1D和胰岛细胞移植，输注体外产生的ag特异性Tr1细胞具有保护作用。然而，Th1细胞的离体复极化既麻烦又昂贵。在我们的体内方法中，我们父母给药CXCL11（“mR-412”），这是一种cxcr3结合配体，我们最近发现它是一种反调节趋化因子。使用CXCL11的长效Fc融合蛋白（“mR-411”）治疗可深刻抑制小鼠实验性过敏性脑脊髓炎（EAE），即使在疾病发作后启动。此外，在过继性转移实验中，从EAE供体中分离出的ag特异性效应Th1细胞在体内经mR-411处理后，可将其定向极化为Tr1细胞，抑制EAE。与泛抑制性免疫调节剂不同，mR-411诱导对活动性疾病具有ag特异性的耐受性，同时保留对先前遇到的抗原的全身免疫。我们现在寻求扩展这些观察结果，并建立mR-412在小鼠T1D模型中建立胰岛免疫耐受的概念证明。具体目标#1：在自发性小鼠T1D模型中建立mR-412挽救治疗糖尿病的效力、剂量依赖性和持久性。mR-412 （0,4,40 ?）g/kg IP 2 X /周)将从180日龄开始给雌性糖尿病NOD小鼠服用18周，这是一个以建立高血糖为特征的时间点。小鼠将在mR-412治疗停止后直接终止（急性组）或在12周后终止（恢复组）。我们将检查胰岛损伤的组织学和免疫组织化学证据，并测定胰岛素含量。检查脾脏和胰腺：1)细胞内细胞因子在淋巴细胞中的表达，2)T细胞亚群浸润和T-bet和STAT3磷酸化的免疫组织化学鉴定。mR-412的血浆浓度将通过ELISA测定，并与功能结果进行比较。我们预计mR-412将恢复正常血糖，直到恢复期结束。支持性数据将包括剂量依赖性证明，mR-412对牺牲时收获的胰岛产生有利的生化和免疫效应，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STAT3磷酸化。