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，我们正在使用一种激动剂刺激细胞，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，配体必须渗透细胞才能发挥活性。适应性免疫反应是否会出现反馈减少，目前还不确定。鉴于这一基本原理，我们认为使用一种激动剂而不是一种确定的拮抗剂是一种独特而创新的方法。本应用的中心假设是口服TLR7类似物可以保护关节免受免疫介导的损伤。这一假设将通过以下具体目的进行检验：1。在两种小鼠炎症性关节炎模型中，评估两种口服TLR7类似物TLR脱敏的相对效力。在不依赖T细胞的关节炎模型中，评估TLR7激动剂对TLR减敏的先天免疫细胞和适应性免疫细胞的相对作用；3：评估口服TLR减敏对适应性免疫反应的影响。我们已经组建了一个研究小组，在药物化学（Cottam）、炎症性疾病小鼠模型（Corr）和先天免疫（Hayashi）方面具有互补的专业知识。这些研究人员的共同努力将比任何一个独立的人能够更快地整合项目的各个阶段。Drs。Cottam， Corr和Hayashi是长期合作伙伴，他们一直在一起研究腺嘌呤和鸟嘌呤类似物的机制，这些类似物具有潜在的临床应用生物学特性。这些化合物将在科塔姆博士的实验室生成，并进行纯度分析。Drs。Corr和Hayashi将负责在早期和确诊疾病中口服和全身效力的体外和体内测试。从长远来看，这些研究的结果可能会增加我们的治疗手段，以减少自身免疫性疾病引起的炎症损伤。

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.