TLR-7 Agonists as Targeted Anti-inflammatory Agents in Arthritis

描述（由申请人提供）：在这个项目中，我们将研究一种免疫刺激剂的新应用。Toll样受体（TLR）的配体刺激先天免疫系统。然而，我们正在使用激动剂来刺激细胞，为下游信号分子创造一个陷阱，以降低它们从其他激活细胞表面受体传递信号的能力。虽然使用激动剂来减少信号传导是违反直觉的，但这种创新的方法可以使免疫系统脱敏并限制炎症反应。我们选择使用TLR7激动剂，因为TLR7是细胞内的，并且配体必须渗透细胞以获得活性。目前还不确定在适应性免疫反应中是否会有反馈减少。鉴于这一基本原理，我们认为使用先天免疫系统的激动剂而不是确定的拮抗剂是一种独特的创新方法。本申请的中心假设是口服可利用的TLR7类似物将保护关节免受免疫介导的损伤。这一假设将与以下具体目标进行测试：1。在两种炎性关节炎的鼠模型中评价用两种口服可用的TLR 7类似物进行TLR脱敏的相对效力，2.评估先天免疫细胞和适应性免疫细胞对于在T细胞非依赖性关节炎模型中使用TLR 7激动剂的TLR减敏的相对作用，以及3：评估口服TLR减敏对适应性免疫应答的作用。我们已经组建了一个研究团队，他们在学术环境中具有药物化学（科塔姆）、炎症性疾病小鼠模型（Corr）和先天免疫（Hayashi）方面的互补专业知识。这些研究人员的共同努力将能够比任何一个单独的人更快地整合项目的各个阶段。科塔姆博士、Corr博士和Hayashi博士是长期合作者，一直在共同研究腺嘌呤和鸟嘌呤类似物的机制，这些类似物表现出潜在的临床应用生物学特性。化合物将在Dr.科塔姆的实验室中生成，并进行纯度分析。Corr和Hayashi博士将负责在早期和已确诊疾病中进行口服和全身效力的体外和体内试验。从长远来看，这些研究的结果可能会增加我们的治疗设备，以减少自身免疫性疾病的炎症损伤。 公共卫生相关性：虽然有几种治疗类风湿性关节炎的生物制剂，但没有一种是普遍有效的，本项目将研究一种口服的新型第二代Toll样受体激动剂的有益免疫调节作用。

DESCRIPTION (provided by applicant): In this project we will investigate a novel application of an immune stimulating agent. Ligands for the Toll-like receptors (TLR) stimulate the innate immune system. However, we are using an agonist to stimulate the cells to create a trap for downstream signaling molecules to reduce their ability to transmit signals from other activating cell surface receptors. Although using an agonist to diminish signaling is counter-intuitive, this innovative approach desensitizes the immune system and limits the inflammatory response. We have chosen to use a TLR7 agonist, as TLR7 is intracellular, and ligands must permeate the cell for activity. It is yet undetermined if there will be feedback reduction in the adaptive immune response. Given this rationale we feel that using an agonist for the innate immune system rather than a defined antagonist is a unique and innovative approach. The central hypothesis of this application is that an orally available TLR7 analog will protect the joint from immune mediated damage. This hypothesis will be tested with the following specific aims: 1. Evaluate the relative potency of TLR desensitization with two orally available TLR7 analogs in two murine models of inflammatory arthritis, 2. Assess the relative roles of innate and adaptive immune cells for TLR hyposensitization with TLR7 agonists in T cell independent model of arthritis, and 3: Assess the effect of oral TLR hyposensitization on adaptive immune responses. We have assembled a team of investigators with complementary expertise in medicinal chemistry (Cottam), murine models of inflammatory disease (Corr), and innate immunity (Hayashi) within an academic setting. The combined efforts of these investigators will be able to more rapidly integrate the phases of the project than any single one could independently. Drs. Cottam, Corr and Hayashi are long standing collaborators and have been working together to investigate the mechanisms of adenine and guanine analogs that exhibit biologic properties of potential clinical application. The compounds will be generated in Dr. Cottam's laboratory and analyzed for purity. Drs. Corr and Hayashi will be responsible for the in vitro and in vivo testing for oral and systemic potency in early and established disease. In the long term the results of these investigations might lead to additions in our therapeutic armamentarium to reduce the inflammatory damage from autoimmune disease. PUBLIC HEALTH RELEVANCE: Although there are several biologic agents that treat rheumatoid arthritis none are universally effective, This project will examine the beneficial immunomodulatory effects of a novel second generation Toll- like receptor agonist that is orally available.