Tr1-Specific Tolerance: a Novel Treatment of Multiple Sclerosis

Tr1 特异性耐受：多发性硬化症的新疗法

• 批准号: 8195653
• 负责人: Kanneganti Murthy
• 金额: $ 31.95万
• 依托单位: RADIKAL THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195653
• 关键词: Acute; Address; Adoptive Transfer; Aftercare; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autoantigens; Autoimmune Diseases; Binding Sites; Bypass; CD28 gene; CD4 Positive T Lymphocytes; CD46 Antigen; CXC chemokine receptor 3; CXCL10 gene; CXCL11 gene; CXCL9 gene; CXCR3 gene; Calcineurin inhibitor; Cell physiology; Cells; Cellular Immunity; Chimeric Proteins; Clinical; Control Groups; Defect; Deterioration; Dexamethasone; Disease; Equilibrium; Etiology; Experimental Autoimmune Encephalomyelitis; FDA approved; Functional disorder; Grant; Histologic; Homologous Gene; Human; IL2RA gene; IgG1; Immune Tolerance; Immunity; Immunosuppressive Agents; In Vitro; Incubated; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Ligand Binding; Location; Mediating; Mitoxantrone; Modeling; Monitor; Multiple Sclerosis; Mus; Myelin; Neurologic; Neurons; Onset of illness; Paralysed; Pathway interactions; Patients; Pharmacodynamics; Phase; Phenotype; Phosphorylation; Primates; Production; Property; Receptor Signaling; Recombinant Proteins; Regulatory T-Lymphocyte; Relapse; Relapsing-Remitting Multiple Sclerosis; Relative (related person); Research Design; STAT3 gene; Safety; Severity of illness; Signal Transduction; Sirolimus; Spinal Cord; Spleen; Steroids; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissues; Titrations; Transgenic Organisms; Work; chemokine; copolymer 1; human FRAP1 protein; in vivo; innovation; interferon therapy; lymph nodes; mouse model; natalizumab; novel; receptor; response; transcription factor

DESCRIPTION (provided by applicant): We are developing a novel immunomodulatory therapy, hR-411, to treat relapsing-remitting multiple sclerosis (RRMS). hR-411 restores regulatory T-cell balance by redirecting pathogenic Th1/Th17 cells into tolerance- inducing Tr1 cells. hR-411 is formed from the fusion of human Ig-Fc and CXCL11, a CXCR3-binding ligand that has been recently identified as a counter-regulatory chemokine. In contrast to the pro-inflammatory CXCR3- binding ligands CXCL9 and CXCL10, in vitro exposure of inflammatory effector Th1 and Th17 cells to CXCL11 redirects their polarization into anti-inflammatory Tr1 (FOXp3-CD25-IL-10high) cells. mR-411, the murine homologue of hR-411, profoundly suppresses the neurological and histologic findings of murine EAE, even when initiated after disease onset. The durability of this repolarization is shown in adoptive transfer studies wherein Ag-specific effector Th1 cells isolated from murine EAE donors treated in vivo with mR-411 suppress EAE in recipients with active disease. In contrast to general immunosupresants (steroids, rapamycin, calcineurin inhibitors), mR-411 induces tolerance that is Ag-specific for active disease yet preserves historical cell-mediated immunity to unrelated Ag's. Because CXCL11 interacts via the CXCR3 receptor, it is expected to bypass the CD46 defect in CD4+ cells in MS and fully activate IL-10 expression and induce Tr1 cell polarization. In support of this assumption, CXCL11 strongly induces IL-10 expression in human CD4+ cells co-incubated in vitro with anti-CD28. The purpose of this grant is to establish the pharmacodyamic profile of mR-411 in a classic murine EAE model of relapsing MS ("R-EAE"). The scientific hypothesis to be tested is that mR-411 decreases R-EAE by inhibiting the activation and differentiation of autoantigen-specific pro-inflammatory Th1/Th17 responses predominantly by promoting the activation of Tr1 cell function. Aim #1: Establish a pharmacodynamic profile of mR-411 in a murine model of R-EAE A titration of mR-411 (1, 3, or 10 mg/kg QOD IP) or an irrelevant IgG1 control will be tested in R-EAE, with groups of mice receiving treatment after the acute phase of disease (16-21 days). These treatment groups will be compared to a negative (sham) control group not exposed to PLP139-151, and a positive control group treated with dexamethasone. Animals will be monitored for overt neurological deterioration over a period of 1 month. Spinal cord tissue will be examined for histologic evidence of inflammation and tissue injury. Aim #2: Determination of the in vivo mechanism by which mR-411 decreases disease severity in R-EAE We will test the working hypothesis that mR-411 treatment decreases EAE disease severity by inhibiting the activation of autoantigen-specific Th1/Th17 effector responses. The same experimental paradigm will be employed as in Aim #1. We wil determine how mR-411 treatment alters the number, phenotype, induction, and function of CD4+ Th1/Th17 cells present within the CNS, spleen, and draining lymph nodes following treatment. These studies will use a combination of actively induced and transfer models of EAE employing myelin-specific 5B6 PLP139-151-specific TCR transgenic T cells. PUBLIC HEALTH RELEVANCE: The proposed studies are designed to determine a putative mechanism by which treatment of mice with mR-411, a counter-regulatory tolerance-inducing chemokine fusion protein, may augment regulatory T cell function, thereby specifically suppressing the activity of autoreactive Th1/17 T cells in a mouse model of the relapsing remitting form of multiple sclerosis. This work has important implications for the etiology and treatment of multiple sclerosis.

描述（由申请人提供）： 我们正在开发一种新型的免疫调节疗法HR-411，以治疗复发性多发性硬化症（RRMS）。 HR-411通过将致病性TH1/TH17细胞重定向到耐受性诱导TR1细胞来恢复调节性T细胞的平衡。 HR-411由人Ig-Fc和CxCl11的融合形成，这是一种CXCR3结合配体，最近被鉴定为反调节趋化因子。与促炎的CXCR3结合配体CXCL9和CXCL10相反，炎症效应子Th1和Th17细胞在体外暴露于CXCL11将其极化重定向到抗炎TR1（Foxp3-CD25-IL-10HIGH）中。 MR-411是HR-411的鼠类同源物，即使在疾病发作后开始，即使在疾病后开始，也深刻抑制了鼠EAE的神经系统和组织学发现。这种复极化的耐用性显示在收养转移研究中，其中Ag特异性效应物Th1细胞从用MR-411在体内治疗的鼠EAE供体分离出来，可抑制活性疾病的受体中的EAE。与普通免疫抑制剂（类固醇，雷帕霉素，钙调神经蛋白抑制剂）相比，MR-411诱导了AG特异性的耐受性，该耐受性可用于活性疾病，但可以保留对无关AG的历史细胞介导的免疫。由于CXCL11通过CXCR3受体相互作用，因此有望绕过MS中CD46+细胞中的CD46缺陷，并完全激活IL-10表达并诱导TR1细胞极化。为了支持这一假设，CXCL11强烈诱导与抗CD28在体外共孵育的人CD4+细胞中IL-10的表达。这笔赠款的目的是在经典的MS（“ R-EAE”）的经典Murine EAE模型中建立MR-411的药物学位剖面。要检验的科学假设是，MR-411通过抑制自身抗原特异性促炎性TH1/TH17反应的激活和分化，主要通过促进TR1细胞功能的激活而降低R-EAE。 AIM＃1：在R-EAE的鼠模型中建立MR-411的药效学特征（1、3或10 mg/kg QOD QOD IP）或一个无关的IgG1对照，将在R-EAE中测试R-EAE，并在疾病急诊期（16-21天急诊阶段）接受治疗后接受R-EAE。将将这些治疗组与未暴露于PLP139-151的阴性（假）对照组以及用地塞米松治疗的阳性对照组进行比较。在1个月内，将监测动物的明显神经系统恶化。将检查脊髓组织的炎症和组织损伤的组织学证据。目的＃2：确定MR-411降低R-EAE疾病严重程度的体内机制，我们将测试以下假设：MR-411治疗通过抑制自身抗原特异性TH1/TH17效应子的激活来降低EAE疾病的严重程度。与AIM＃1相同的实验范式。我们将确定MR-411治疗如何改变CNS，脾脏和排水淋巴结中CD4+ TH1/TH17细胞的数量，表型，诱导和功能。这些研究将使用使用髓磷脂特异性5B6 PLP139-151特异性TCR转基因T细胞的EAE主动诱导和转移模型的组合。 公共卫生相关性： 拟议的研究旨在确定一种假定的机制，通过该机制，MR-411对小鼠的处理是一种反调节耐受性的趋化因子融合蛋白，可能会增强调节性T细胞功能，从而特别抑制自动诱导性TH1/17 T细胞在复发形式的小鼠模型中的自动反应性TH1/17 T细胞的活性。这项工作对多发性硬化症的病因和治疗具有重要意义。