Immune tolerance in the therapy of rheumatoid arthritis

类风湿性关节炎治疗中的免疫耐受

• 批准号: 8052528
• 负责人: Salvatore Albani
• 金额: $ 33.73万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-12 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052528
• 关键词: Immune Tolerance; Rheumatoid Arthritis

DESCRIPTION (provided by applicant): There are few published data concerning the induction and maintenance of immune tolerance based on concurrent clinical and mechanistic studies in rheumatoid arthritis (RA). It is of critical importance to understand the mechanisms of the induction of tolerance because the approach may be effective in maintaining disease control once the initial, symptomatic immune activation has been controlled by currently used therapies. We have recently concluded a NIH-sponsored placebo-controlled pilot phase II trial of mucosal tolerization to dnaJP1 in RA. dnaJP1 is a heat shock protein-derived peptide we previously identified as a contributor of T cell-mediated inflammation in RA. dnaJP1 treatment led to detectable clinical efficacy, which correlated with a significant reduction in the production of pro-inflammatory cytokine TNFa by T cells in response to dnaJP1 in vitro. Hypothesis-generating preliminary studies suggest that epitope-specific therapy affects T cell lineage commitment, resulting in a change from a pro-inflammatory (TH-1 and TH-17) to regulatory function. This is particularly evident in patients pre-treated with hydroxychloroquine (HCQ). These patients had a better clinical response to the dnaJP1 treatment. Pre-treatment with HCQ may induce a novel type of regulatory T cells (Treg), whose presence is necessary for the induction of tolerance. Therefore the hypotheses for this study are: i) epitope-specific therapy has a direct effect on the relative representation and function of T cell lineages within the gradient comprised from TH-1/TH-17 pro-inflammatory effector T cells (Teff) to Treg/ tolerogenic cells; ii) changes in the APC are induced by treatment with HCQ and are prodromic to the generation of a novel type of regulatory T cells, which is identified by the expression of PD-1; iii) The effects of therapy are initially peptide-specific and subsequently affect both innate and adaptive immunity. The objectives are: i) To demonstrate that therapy induces the emergence of various types of T cells with regulatory function that: a) act as suppressors for effector cells, thus favoring an immune deviation; b) can directly lyse antigen presenting cells (APC) which at the same time present dnaJP1 on their HLA and express the appropriate ligands (i.e. express PD-1 ligands to bind PD-1 Treg); ii) To characterize the nature and entity of the therapy-induced immune deviation in Teff from TH-1/TH-17 to a more tolerogenic phenotype; iii) To characterize the "adjuvant" role that HCQ has on the mechanism of tolerization, with a specific focus on HCQ-induced changes in APC phenotype and function. Specific Aim 1: To identify sub-populations of Treg based on co-expression of PD-1, characterize their function in relationship to immune tolerization to dnaJP1, and evaluate their suppressor/regulatory activity on Teff as well as on APC. Specific Aim 2: To characterize the nature and mechanisms of the treatment-induced immune deviation of Teff from pro- inflammatory TH-1/TH-17 to a tolerogenic status. Specific Aim 3: To study treatment-induced changes in APC function, with a specific focus on the "adjuvant" role that HCQ may have in facilitating the expression of a membrane phenotype capable of inducing and engaging T cell with a regulatory/suppressor potential. Our program is developing a novel approach that directly addresses the need of a tolerogen as a complement to currently used biologics. The research plan proposed here relies on a "bedside back to bench" reverse translational itinerary and is a fundamental part of the project, as it will dissect and define the mechanisms of tolerance from a unique collection of samples already obtained from a NIH-funded Phase II trial. These studies have the potential to provide valuable information regarding the immunology of human immune tolerance and will also help translate basic immunology concepts into novel tools for designing better trials and predicting treatment efficacy to optimize a patient's care regimen.

描述（由申请人提供）：关于类风湿关节炎（RA）的同时临床和机理研究，很少有关于免疫耐受性诱导和维持免疫耐受性的数据。了解耐受性诱导的机制至关重要，因为一旦初始症状免疫激活已通过当前使用的疗法控制，该方法可能有效地维持疾病控制。最近，我们结束了一项由NIH赞助的安慰剂控制的试点II期试验，对RA中的DNAJP1粘膜耐受性。 DNAJP1是一种热休克蛋白来源的肽，我们先前鉴定为T细胞介导的RA中炎症的贡献者。 DNAJP1治疗导致了可检测的临床功效，这与T细胞在体外对DNAJP1响应DNAJP1促进促炎性细胞因子TNFA的产生显着降低。假设生成的初步研究表明，表位特异性治疗会影响T细胞谱系的承诺，从而导致从促炎（TH-1和TH-17）转变为调节功能。这在预先治疗羟氯喹（HCQ）的患者中尤其明显。这些患者对DNAJP1治疗的临床反应更好。用HCQ进行预处理可能会诱导一种新型的调节T细胞（TREG），其存在对于诱导耐受性是必要的。因此，这项研究的假设是：i）表位特异性治疗对梯度内T细胞谱系的相对表示和功能有直接影响，该梯度由TH-1/ TH-17促炎性效应T细胞（TEFF）与TREG/耐受性细胞组成； ii）APC的变化是通过用HCQ处理诱导的，并且是对新型调节T细胞的产生的前瞻性，该细胞通过PD-1的表达鉴定出来。 iii）治疗的作用最初是特定于肽的，随后会影响先天和适应性免疫。目的是：i）证明治疗诱导具有调节功能的各种T细胞的出现：a）充当效应细胞的抑制剂，从而有利于免疫偏差； b）可以直接裂解抗原呈现细胞（APC），同时呈现DNAJP1在其HLA上并表达适当的配体（即表示PD-1配体以结合PD-1 Treg）； ii）表征TEFF从TH-1/TH-17到更耐受性表型的TEFF诱导的免疫偏差的性质和实体； iii）表征HCQ在耐受机制中的“辅助”作用，并特别关注HCQ诱导的APC表型和功能变化。具体目的1：基于PD-1的共表达来鉴定Treg的亚群，表征了它们与DNAJP1免疫耐受性关系的功能，并评估其对TEFF和APC的抑制/调节活性。具体目的2：表征TEFF从炎症性TH-1/TH-17到耐受性状态的TEFF的免疫偏差的性质和机制。特定目的3：研究治疗诱导的APC功能的变化，特别关注HCQ在促进膜表型表达的“辅助”作用上，能够具有调节/抑制剂潜力的膜表型的表达。我们的计划正在开发一种新颖的方法，该方法直接解决了对当前使用的生物制剂的补充。此处提出的研究计划依赖于“床头回到长凳”的反向翻译行程，是项目的基本组成部分，因为它将从已从NIH资助的II期试验中获得的独特样本集合中解剖和定义耐受性的机制。这些研究有可能提供有关人免疫耐受性免疫学的有价值的信息，还将有助于将基本免疫学概念转化为新的工具，以设计更好的试验并预测治疗效果以优化患者的护理方案。