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Immune tolerance in the therapy of rheumatoid arthritis

类风湿性关节炎治疗中的免疫耐受

基本信息

批准号：
7912931
负责人：
Salvatore Albani
金额：
$ 38.2万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
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

项目摘要

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）：基于类风湿性关节炎（RA）的同时临床和机制研究，关于诱导和维持免疫耐受的公开数据很少。了解诱导耐受的机制至关重要，因为一旦当前使用的疗法控制了最初的症状性免疫激活，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 资助、安慰剂对照的 RA 粘膜对 dnaJP1 耐受的 II 期试验。 dnaJP1 是一种热休克蛋白衍生肽，我们之前确定它是 RA 中 T 细胞介导的炎症的贡献者。 dnaJP1 治疗产生了可检测的临床疗效，这与体外对 dnaJP1 反应时 T 细胞产生的促炎细胞因子 TNFa 的显着减少相关。假设生成的初步研究表明，表位特异性治疗会影响 T 细胞谱系定向，导致从促炎症（TH-1 和 TH-17）功能转变为调节功能。这在接受过羟氯喹（HCQ）治疗的患者中尤其明显。这些患者对 dnaJP1 治疗有更好的临床反应。用 HCQ 预处理可能会诱导一种新型的调节性 T 细胞 (Treg)，其存在对于诱导耐受是必要的。因此，本研究的假设是： i) 表位特异性治疗对从 TH-1/TH-17 促炎效应 T 细胞 (Teff) 到 Treg/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有直接影响； ii) APC 的变化是由 HCQ 治疗引起的，并且是一种新型调节性 T 细胞产生的前兆，这种细胞可通过 PD-1 的表达来识别； iii) 治疗效果最初是肽特异性的，随后影响先天免疫和适应性免疫。目标是： i) 证明治疗可诱导具有调节功能的各种类型 T 细胞的出现，这些细胞： a) 作为效应细胞的抑制因子，从而有利于免疫偏差； b) 可以直接裂解抗原呈递细胞（APC），同时在其 HLA 上呈递 dnaJP1 并表达适当的配体（即表达 PD-1 配体以结合 PD-1 Treg）； ii) 表征治疗诱导的 Teff 免疫偏差的性质和实体，从 TH-1/TH-17 转向更具耐受性的表型； iii) 描述 HCQ 对耐受机制的“佐剂”作用，特别关注 HCQ 诱导的 APC 表型和功能变化。具体目标 1：基于 PD-1 的共表达鉴定 Treg 亚群，表征其与 dnaJP1 免疫耐受相关的功能，并评估其对 Teff 和 APC 的抑制/调节活性。具体目标 2：表征治疗诱导的 Teff 从促炎性 TH-1/TH-17 到耐受性状态的免疫偏差的性质和机制。具体目标 3：研究治疗诱导的 APC 功能变化，特别关注 HCQ 在促进膜表型表达方面可能具有的“佐剂”作用，该膜表型能够诱导和参与具有调节/抑制潜力的 T 细胞。我们的项目正在开发一种新方法，可以直接满足耐受原的需求，作为当前使用的生物制剂的补充。这里提出的研究计划依赖于“床边回到工作台”的反向转化行程，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的免疫学的有价值的信息，并且还将有助于将基本的免疫学概念转化为新的工具，以设计更好的试验和预测治疗效果，以优化患者的护理方案。