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: 8328926
• 负责人: Kanneganti Murthy
• 金额: $ 30.35万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328926
• 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.

描述(由申请人提供)： 我们正在开发一种新的免疫调节疗法，HR-411，用于治疗复发-缓解型多发性硬化症(RRMS)。HR-411通过将致病的Th1/Th17细胞重定向为诱导耐受的TR1细胞来恢复调节性T细胞平衡。HR-411是由人Ig-Fc和CXCL11融合而成的，CXCL11是一种CXCR3结合配体，最近被发现是一种反调节趋化因子。与促炎症的CXCR3结合配体CXCL9和CXCL10不同，炎症效应细胞Th1和Th17在体外暴露于CXCL11会将它们的极化重定向到抗炎TR1(Foxp3-CD25-IL-10High)细胞。MR-411是HR-411的小鼠同系物，即使在疾病发作后启动，也能深刻抑制小鼠EAE的神经学和组织学发现。这种复极化的持久性在过继转移研究中得到了证明，在过继转移研究中，从用MR-411活体治疗的小鼠EAE捐赠者中分离出的Ag特异性效应Th1细胞抑制了患有活动期疾病的受者的EAE。与一般免疫抑制剂(类固醇、雷帕霉素、钙调神经磷酸酶抑制剂)不同，MR-411可诱导对活动期疾病的抗原特异性耐受，但保留了以往对无关抗原的细胞免疫。由于CXCL11通过CXCR3受体相互作用，有望绕过MS患者CD4+细胞中的CD46缺陷，充分激活IL-10的表达并诱导TR1细胞极化。为了支持这一假设，CXCL11在体外与抗CD28共孵育的人CD4+细胞中强烈诱导IL-10的表达。这笔赠款的目的是在复发性多发性硬化症(“R-EAE”)的经典小鼠EAE模型中建立MR-411的药代动力学特征。有待检验的科学假设是，MR-411通过抑制自身抗原特异性的促炎Th1/Th17反应的激活和分化，主要是通过促进TR1细胞功能的激活来降低R-EAE。目的#1：在R-EAE小鼠模型中建立MR-411的药效学模型。在R-EAE中，将测试MR-411(1、3或10 mg/kg，qod ip)的滴定或无关的IgG1对照，并在疾病急性期(16-21天)后接受治疗。这些治疗组将与未接触PLP139-151的阴性(假)对照组和接受地塞米松治疗的阳性对照组进行比较。动物将在一个月的时间里接受明显的神经恶化监测。将对脊髓组织进行检查，以寻找炎症和组织损伤的组织学证据。目的#2：MR-411降低R-EAE疾病严重程度的体内机制的确定我们将验证MR-411治疗通过抑制自身抗原特异性Th1/Th17效应反应的激活来降低EAE疾病严重程度的工作假设。我们将采用与目标1相同的实验范式。我们将确定MR-411治疗如何改变存在于中枢神经系统、脾和引流淋巴结中的CD4+Th1/Th17细胞的数量、表型、诱导和功能。这些研究将使用主动诱导和转移模型的组合，使用髓鞘特异性5B6 PLP139-151特异性TCR转基因T细胞。