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（由申请方提供）：基于类风湿性关节炎（RA）的同期临床和机制研究，关于诱导和维持免疫耐受的已发表数据很少。理解诱导耐受的机制是至关重要的，因为一旦最初的、症状性的免疫激活被当前使用的疗法控制，该方法可能有效地维持疾病控制。我们最近完成了一项由NIH赞助的安慰剂对照试验性II期临床试验，研究RA患者对dnaJP 1的粘膜耐受性。dnaJP 1是一种热休克蛋白衍生的肽，我们以前确定为RA中T细胞介导的炎症的贡献者。dnaJP 1治疗导致可检测的临床功效，其与体外响应于dnaJP 1的T细胞产生促炎细胞因子TNF α的显著减少相关。假设产生的初步研究表明，表位特异性治疗影响T细胞谱系定型，导致从促炎性（TH-1和TH-17）到调节功能的变化。这在用羟氯喹（HCQ）预治疗的患者中尤其明显。这些患者对dnaJP 1治疗有更好的临床反应。用HCQ预处理可以诱导一种新型的调节性T细胞（Treg），其存在是诱导耐受所必需的。i）表位特异性治疗对从TH-1/TH-17促炎效应T细胞（Teff）到Treg/致耐受性细胞组成的梯度内T细胞谱系的相对代表性和功能具有直接影响; ii）APC的变化由HCQ处理诱导，并且是产生新型调节性T细胞的前驱，其通过PD-1的表达来鉴定; iii）治疗的效果最初是肽特异性的，随后影响先天免疫和适应性免疫。其目标是：i）证明治疗诱导具有调节功能的各种类型的T细胞的出现，所述调节功能：a）充当效应细胞的抑制剂，从而有利于免疫偏离; B）可以直接裂解抗原呈递细胞（APC），所述抗原呈递细胞同时在其HLA上呈递dnaJP 1并表达适当的配体ii）表征Teff中从TH-1/TH-17到更具耐受性表型的治疗诱导的免疫偏离的性质和实体; iii）表征HCQ对耐受化机制的“佐剂”作用，特别关注HCQ诱导的APC表型和功能的变化。具体目标1：鉴定基于PD-1共表达的Treg亚群，表征其与对dnaJP 1的免疫耐受相关的功能，并评价其对Teff以及对APC的抑制/调节活性。具体目标二：表征Teff从促炎性TH-1/TH-17到致耐受性状态的治疗诱导的免疫偏离的性质和机制。具体目标3：研究治疗诱导的APC功能变化，特别关注HCQ在促进能够诱导和接合具有调节/抑制潜力的T细胞的膜表型表达中可能具有的“佐剂”作用。我们的项目正在开发一种新的方法，直接解决耐受原作为目前使用的生物制剂的补充的需求。这里提出的研究计划依赖于“床边回到长凳”的反向翻译路线，是该项目的基本组成部分，因为它将从NIH资助的II期试验中获得的独特样本集合中剖析和定义耐受机制。这些研究有可能提供有关人类免疫耐受免疫学的有价值信息，也将有助于将基本免疫学概念转化为新工具，用于设计更好的试验和预测治疗效果，以优化患者的护理方案。