Discovering a novel therapy for RA patients

类风湿性关节炎(RA)是最常见的自身免疫性疾病，在中国有250万人患病 美国，其中许多是退伍军人。四分之一的退伍军人患有关节炎(25.6%)，而1/4的退伍军人患有关节炎 五名平民。类风湿关节炎是一种慢性、致残性自身免疫性疾病，身体会攻击自己的组织。作为RA 随着病情的进展，进行简单的日常活动对患有 疾病。类风湿性关节炎无法治愈，高达50%的患者对循环中的抗肿瘤坏死因子治疗没有反应 阻断肿瘤坏死因子后，Th17/IL-17水平显著升高。对于这一亚群的RA患者来说， 一种新的途径削弱了肿瘤坏死因子和白介素17之间的协同作用，可能提供了另一种选择 治疗。有效的治疗可以使所有患有类风湿关节炎的现役和退役军人和退伍军人以及 他们的家人和朋友可能患有类风湿性关节炎。导致新疗法的发现将使退伍军人管理局受益 通过降低医疗和手术护理费用来减少人员；除了继发性RA并发症 包括抑郁、心血管疾病和心理社会压力。因此，有效的类风湿关节炎治疗将 改善退役老兵的痛苦和生活质量。 我们发现，与正常巨噬细胞相比，类风湿关节炎患者Toll样受体(TLR)5水平显著升高。 其表达与RA疾病活动性评分(DAS28)密切相关。我们还演示了TLR5 RA滑液中存在天然配体。TLR5与其天然配体的连接，转化RA 外周血(PB)幼稚细胞转化为经典的M1巨噬细胞(MφS)，可产生高水平的肿瘤坏死因子、白介素6 和IL-1β。此外，IL-6和IL-1β由TLR5驱动的M1 MφS产生，可分化为幼稚T细胞 转化为分泌IL-17的炎性RA Th17细胞。小鼠全身和局部注射TLR5激动剂 加剧关节肿胀。 本研究的目的是了解TLR5功能的细胞和分子机制 并评价TLR5抗体能否作为RA治疗的一种有前景的策略。我们 假设结扎关节TLR5触发促炎M-φ、S和T细胞的分化，从而可以 最终将类风湿关节炎的炎症过程扩展到侵蚀性阶段。我们进一步假设，一种新的TLR5 我们实验室产生的AB可能是无反应者的一种替代治疗策略，因为它否定了 类风湿关节炎中效应髓系细胞和淋巴样细胞的相互作用。 为了验证我们的假设，我们将检验RA Mϕ和T细胞与内皮细胞的串扰的贡献 细胞对骨新生血管的影响。随后，建立临床前期疗效，TLR5单抗治疗 将与目前在RA细胞和临床前模型中可用的治疗方法进行比较。成功 该项目的完成将确定一种新的机制，将效应髓系细胞的功能与 以及建立一种新的治疗策略，用于治疗对 目前的治疗方法。

Rheumatoid arthritis (RA) is the most common autoimmune disease which affects 2.5 million people in US, many of which are VA military personnel. One in four veterans has arthritis (25.6%), compared to one in five civilians. RA is a chronic, disabling autoimmune disease in which the body attacks its own tissues. As RA progresses, performing simple daily activities can become increasingly difficult for patients suffering from the disease. There is no cure for RA and up to 50% of patients do not respond to anti-TNF therapies as circulating Th17/IL-17 levels are highly elevated subsequent to TNF blockade. For this subset of RA patients, disruption of a novel pathway that impairs the synergy between TNF and IL-17 cascades may provide an alternative treatment. Effective therapies can benefit all active and retired military and VA members with RA, as well as their families and friends who may suffer from RA. Findings that lead to new therapy will benefit the VA personnel by reducing the cost for medical and surgical care; in addition to the secondary RA complications including depression, cardiovascular disease and psychosocial stress. Consequently, effective RA therapy will improve the pain & the life quality of the retired veterans. We discovered that toll like receptor (TLR)5 is highly elevated in RA compared to normal macrophages, and its expression closely correlates with RA disease activity score (DAS28). We also demonstrated that TLR5 natural ligands are present in RA synovial fluid. Ligation of TLR5 to its natural ligands, transforms RA peripheral blood (PB) naïve cells into classical M1 macrophages (Mφs) which produce high levels of TNF, IL-6 and IL-1β. In addition, IL-6 and IL-1β produced from TLR5 driven M1 Mφs can differentiate the naïve T cells into inflammatory RA Th17 cells that secrete IL-17. In mice, systemic and local injection of a TLR5 agonist exacerbates joint swelling. The objective of this proposal is to understand the cellular and molecular mechanisms of TLR5 function and to evaluate whether TLR5 antibody (Ab) can be utilized as a promising strategy for RA therapy. We hypothesize that ligation of joint TLR5 triggers differentiation of proinflammatory Mφs and T cells which can ultimately expand the RA inflammatory process to the erosive phase. We further postulate that a novel TLR5 Ab generated by our lab may be an alternative treatment strategy for non-responders as it negates the interaction of effector myeloid and lymphoid cells in RA. To test our hypothesis, we will examine the contribution of RA Mϕ and T cell cross talk with endothelial cells on bone neovascularization. Subsequently, to establish the preclinical stage efficacy, TLR5 Ab therapy will be compared to the currently available treatments in RA cells and preclinical models. Successful completion of this project will identify a novel mechanism that links the function of effector myeloid cells to lymphoid cells as well as establishing a novel treatment strategy for RA patients that do not respond to the current therapies.