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的细胞表面受体传递信号的能力。尽管使用激动剂来减少信号传递是违反直觉的，但这种创新的方法会使免疫系统变得不敏感，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，配体必须渗透到细胞才能发挥活性。目前尚不确定获得性免疫反应中是否会出现反馈减少。鉴于这一原理，我们认为，使用先天免疫系统的激动剂而不是明确的拮抗剂是一种独特和创新的方法。这一应用的中心假设是口服的TLR7类似物将保护关节免受免疫介导的损害。这一假说将以以下具体目标进行验证：1.评估两种口服TLR7类似物在两种炎症性关节炎小鼠模型中TLR脱敏的相对效力；2.在T细胞非依赖性关节炎模型中，评估天然免疫细胞和获得性免疫细胞对TLR7激动剂TLR减敏的相对作用；3：评估口服TLR减敏对适应性免疫反应的影响。我们组建了一支在药物化学(Cottam)、炎症性疾病小鼠模型(Corr)和先天免疫(Hayashi)方面具有互补专业知识的研究团队。这些调查人员的共同努力将能够比任何一个单独的调查人员更快地整合项目的各个阶段。Cottam博士、Corr博士和Hayashi博士是长期的合作伙伴，他们一直在合作研究腺嘌呤和鸟嘌呤类似物的机制，这些机制显示出潜在的临床应用的生物学特性。这些化合物将在科塔姆博士的实验室中产生，并进行纯度分析。Corr博士和Hayashi博士将负责对早期和已确定的疾病进行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导致我们的治疗性医疗设备的增加，以减少自身免疫性疾病造成的炎性损害。

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.