Small molecule target for suppression of autoimmunity in rheumatoid arthritis

描述(由申请人提供)：在人类研究中，促炎症细胞因子IL-17与关节破坏和类风湿性关节炎(RA)的炎症发病机制有关。在RA动物模型中，靶向删除或抑制IL-17可显著降低疾病严重程度。最近发现的一种CD4T细胞谱系，在功能上与更知名的CD4T辅助细胞Th1和Th2不同，表达IL-17，被称为Th-17。IL-23是Th-17细胞的生存因子。由于IL-23基因敲除的动物对RA的诱导具有抵抗力，Th-17细胞在该病的发病机制中具有潜在的重要作用。申请者已经确定了一种孤儿受体的小分子配体，该受体是形成Th-17细胞所必需的，并表明受体拮抗剂可以阻止Th-17从NAVE CD4T细胞分化。在这项研究中，我们建议通过鉴定具有良好药代动力学性质的先导化合物来评估这种新型受体作为RA药物靶点的有效性，以用于在已建立的RA动物模型--小鼠胶原性关节炎(CIA)中进行测试。目前的受体拮抗剂不适合进行明确的体内研究。这项研究的具体目的将包括：(1)与药物化学合作伙伴合成有希望的药物类似物，以提高效力和改善体内试验的代谢稳定性；(2)鉴定CIA引流淋巴结中诱导的主要IL-17 T细胞类型，并表征它们对受体配体的反应；(3)评估铅化合物在CIA中的作用，包括在疾病诱导期间和从第一次症状出现起(约第30天)，以便更好地了解药物作用的机制。我们还将研究这类新化合物的毒性和二次免疫效应。我们的目标是创造一种全新的口服生物利用型药物来治疗类风湿关节炎，阻断疾病中主要的T细胞介导的免疫发病机制，从而提供一种与类固醇、甲氨蝶呤和其他常规用于治疗类风湿关节炎的小分子药物相比，副作用减少、治疗效果更广泛的有效治疗方法。关于与公共卫生的关系，类风湿性关节炎(RA)是一种痛苦和严重的疾病，影响着200万美国人。针对免疫系统的新药(如恩替西普和英夫利昔单抗)对一些但不是所有患者都有缓解作用，但这些药物也有严重的副作用，可能会限制它们的使用。拟议的研究将迈出第一步，开发一类新的小分子、口服生物可用药物，旨在抑制一种新的、潜在的致病免疫细胞的功能，最近的科学证据有力地表明，这种细胞参与了RA的发病机制。

DESCRIPTION (provided by applicant): The pro-inflammatory cytokine IL-17 has been implicated in joint destruction and in the inflammatory pathogenesis of rheumatoid arthritis (RA) in human studies. Targeted deletion or inhibition of IL-17 leads to significant reduction in disease severity in animal models of RA. A recently discovered lineage of CD4+ T cells, functionally distinct from the better known CD4+ T helper cells Th1 and Th2, expresses IL-17 and is referred to as Th-17. IL-23 is a survival factor for Th-17 cells. Since IL-23 knockout animals are resistant to induction of RA, Th-17 cells are potentially of major importance in the pathogenesis of the disease. The applicants have identified small molecule ligands to an orphan receptor that is required for the formation of Th-17 cells and have shown that receptor antagonists block Th-17 differentiation from na¿ve CD4+ T cells. In this study, we propose to evaluate the utility of this novel receptor as a drug target for RA by identifying lead compounds with good pharmacokinetic properties for testing in murine collagen-induced arthritis (CIA), an established animal model of RA. Current receptor antagonists are not suitable for definitive in vivo studies. The specific aims of this investigation will include: (1) synthesis of analogs to promising drug-like hits with a medicinal chemistry partner in order to increase potency and improve metabolic stability for in vivo testing; (2) identification of the major IL-17+ T cell types induced in CIA draining lymph nodes and characterization of their response to receptor ligands; and (3) evaluation of lead compound effects in CIA both during disease induction and from the time of first symptoms, about day 30, in order to better understand the mechanism of drug effect. The toxicity and secondary immune effects of this new compound class will be investigated as well. Our goal is to create an entirely new class of orally-bioavailable drugs for RA that blocks the major T cell-mediated arm of immune pathogenesis in the disease, thereby providing an efficacious therapy with reduced side effects and broader therapeutic utility in comparison to steroids, methotrexate and other small molecule drugs routinely used for treatment of RA. With regard to relevance to public health, rheumatoid arthritis (RA) is a painful and crippling disease that affects two million Americans. New drugs that target the immune system (such as entanercept and infliximab) have provided relief for some but not all patients, but the drugs also have serious side effects that may limit their use. The proposed studies would take the first step to develop a new class of small molecule, orally-bioavailable drugs designed to inhibit the function of a novel, potentially pathogenic immune cell that recent scientific evidence strongly suggests is involved in the pathogenesis of RA.