Small Molecule Inhibitors of Effector Th-17 Cells in Inflammatory Bowel Disease

描述(申请人提供)：炎症性肠病(IBD)，包括克罗恩病和溃疡性结肠炎(UC)，是一种终生T细胞介导的小肠或结肠炎症状态。在克罗恩病和UC患者的肠道活检组织中，高度促炎细胞因子白介素17(IL-17)与疾病活动性成比例升高，但在未受影响的个体中几乎不存在。最近发现了一类新的效应细胞，称为Th-17细胞，它表达IL-17和其他几种炎性细胞因子。Th-17细胞不同于研究较好的Th1和Th2效应T细胞，是结肠炎和其他类型自身免疫性疾病动物模型中涉及的主要T细胞谱系。申请人已经确定了结构多样化的小分子拮抗剂，它是一种以前未被探索的孤儿受体，是CD4+Th-17细胞分化所必需的。在细胞培养中，这些受体拮抗剂可阻断天然的CD4+T细胞形成Th-17细胞，抑制抗原攻击后记忆性Th-17细胞的扩张，并抑制IL-17的释放。这些发现表明，口服生物利用型小分子拮抗剂将在治疗IBD方面具有显著的治疗潜力。与针对Th-17途径中的关键细胞因子(如IL-17和IL-23)的可注射单抗相比，这一新的小分子治疗类别还将具有显著的治疗优势，例如口服生物利用度和更容易给药。这项建议的具体目的是：(1)证明如果抑制肠道Th-17是新化合物类别的靶点，新型受体拮抗剂如预期那样阻断离体肠组织中IL-17的释放；(2)从Orphagen公司已发现的拮抗剂中合成并表征用于体内研究的小分子铅拮抗剂；以及(3)在已建立的反映Th-17活性的小鼠结肠炎模型中，研究铅拮抗剂对疾病活性的抑制作用，该模型是通过将天然CD4+CD45RBHigh T细胞转移到免疫低下小鼠而诱导的。这项研究中确定的线索将有助于在计划的第二阶段研究中确定治疗IBD和其他自身免疫适应症的潜在临床候选者。与公共卫生相关：克罗恩病和溃疡性结肠炎是慢性肠道疾病，治疗选择有限。目前的药物副作用很大。我们建议表征和开发一类新的小分子药物，这种药物可以抑制一种新的T细胞谱系的形成和功能，这种T细胞似乎在疾病的免疫病理中发挥核心作用。

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), including Crohn's Disease and ulcerative colitis (UC), is a lifelong T cell- mediated inflammatory condition of the small intestine or colon. The highly proinflammatory cytokine interleukin-17 (IL-17) is elevated in proportion to disease activity in intestinal biopsies of both Crohn's and UC patients but is virtually absent in unaffected individuals. A new class of effector CD4+ T cells, known as Th-17 cells, has recently been identified that expresses IL-17 and several other inflammatory cytokines. The Th-17 cell is distinct from the better-studied Th1 and Th2 effector T cells and is the major T cell lineage implicated in animal models of colitis and other types of autoimmune disease. The applicants have identified structurally diverse small molecule antagonists to a previously unexplored orphan receptor that is required for CD4+ Th-17 cell differentiation. In cell culture, these receptor antagonists block Th-17 cell formation from na¿ve CD4+ T cells, inhibit the expansion of memory Th-17 cells following challenge by antigen, and suppress IL-17 release. These findings suggest that an orally bioavailable small molecule antagonist will have significant therapeutic potential in the treatment of IBD. This proposed new small molecule therapeutic class will also have significant therapeutic advantages--such as oral bioavailability and greater ease of administration--over injectable monoclonal antibodies to key cytokines in the Th-17 pathway such as IL-17 and IL-23. The specific aims of this proposal are to: (1) demonstrate that the novel receptor antagonists block IL-17 release in isolated intestinal tissue as expected if suppression of intestinal Th-17 is a target of the new compound class; (2) synthesize and characterize small molecule lead antagonists for in vivo studies from antagonists already identified at Orphagen; and (3) investigate lead antagonist suppression of disease activity in an established model of murine colitis that reflects Th-17 activity and is induced by transfer of na¿ve CD4+CD45RBhigh T cells to immunocompromised mice. Leads identified in this study will facilitate the identification of potential clinical candidates for treatment of IBD and other autoimmune indications in planned Phase II research. PUBLIC HEALTH RELEVANCE: Crohn's disease and ulcerative colitis are chronic, intestinal disorders for which treatment options are limited. The side effects of current medications are significant. We propose to characterize and develop a novel class of small molecule drugs that suppresses the formation and function of a novel lineage of T cells that appear to have a central role in the immune pathology of the disease.