Discovering a novel therapy for RA patients

发现一种治疗 RA 患者的新疗法

• 批准号: 10455411
• 负责人: SHIVA SHAHRARA
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455411
• 关键词: Affect; Agonist; Anti-Tumor Necrosis Factor Therapy; Antibodies; Antibody Therapy; Arthritis; Autoimmune; Autoimmune Diseases; Binding; Black Populations; Blocking Antibodies; Blood Cells; Blood Vessels; Cardiovascular Diseases; Caring; Cell Communication; Cell Maturation; Cell Proliferation; Cell model; Cells; Chronic; Clinic; Collagen Arthritis; Connective Tissue Diseases; Custom; Development; Disease; Dose; Effectiveness; Endothelial Cells; Engineering; Family; Flagellin; Friends; Genes; Goals; Hispanic Populations; Human; Human Engineering; Human Resources; Impairment; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Injections; Interdisciplinary Study; Interleukin-1; Interleukin-1 beta; Interleukin-17; Interleukin-6; Joints; Lead; Ligands; Ligation; Link; Lymphoid Cell; Mediating; Medical Care Costs; Mental Depression; Military Personnel; Molecular; Mus; Myelogenous; Myeloid Cells; Operative Surgical Procedures; Osteoclasts; Oxidative Stress; Pain; Pathway interactions; Patients; Persons; Phase; Play; Pre-Clinical Model; Process; Psychosocial Stress; Quality of life; Research Personnel; Rheumatoid Arthritis; Role; Secondary to; Severities; Specimen; Synovial Fluid; T-Lymphocyte; TLR5 gene; TNF gene; Testing; Therapeutic; Tissues; Veterans; War; Woman; alternative treatment; antibody engineering; arthritis therapy; blood vessel development; bone; bone erosion; cell type; conditional knockout; effective therapy; efficacy evaluation; experience; improved; joint destruction; joint inflammation; macrophage; member; monocyte; mouse model; neovascularization; novel; novel therapeutics; oxidative damage; peripheral blood; pre-clinical; receptor; research clinical testing; side effect; synergism; trafficking; treatment strategy

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.

风湿性关节炎（RA）是最常见的自身免疫性疾病， 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%），相比之下， 五个平民类风湿关节炎是一种慢性、致残性自身免疫性疾病，其中身体攻击自身组织。诸如RA 随着疾病的进展，进行简单的日常活动对于患有糖尿病的患者来说可能变得越来越困难。 疾病RA无法治愈，高达50%的患者对抗TNF治疗无反应， TNF阻断后Th 17/IL-17水平高度升高。对于RA患者的这一子集， 一种削弱TNF和IL-17级联之间协同作用的新途径可能提供一种替代方法， 治疗有效的治疗方法可以使所有现役和退役军人和退伍军人协会成员受益， 他们的家人和朋友谁可能患有类风湿关节炎。导致新疗法的发现将使VA受益 通过降低医疗和手术护理费用;除了继发性RA并发症 包括抑郁症、心血管疾病和心理压力。因此，有效的RA治疗将 改善退伍军人的痛苦和生活质量。 我们发现，与正常巨噬细胞相比，Toll样受体（TLR）5在RA中高度升高， 其表达与RA疾病活动度评分（DAS 28）密切相关。我们还证明了TLR 5 天然配体存在于RA滑液中。TLR 5与其天然配体的连接，转化RA 外周血（PB）幼稚细胞转化为产生高水平TNF、IL-6的经典M1巨噬细胞（Mφ） 和IL-1β。此外，TLR 5驱动的M1 Mφ产生的IL-6和IL-1β可诱导幼稚T细胞分化 分泌IL-17的炎症性RA Th 17细胞。在小鼠中，全身和局部注射TLR 5激动剂， 加剧关节肿胀。 本提案的目的是了解TLR 5功能的细胞和分子机制 并评价TLR 5抗体（Ab）是否可作为RA治疗的一个有希望的策略。我们 假设关节TLR 5的连接触发了促炎性Mφ和T细胞的分化， 最终将RA炎症过程扩展到糜烂阶段。我们进一步假设，一种新的TLR 5 我们实验室产生的抗体可能是无应答者的替代治疗策略，因为它否定了 类风湿关节炎中髓样和淋巴样效应细胞的相互作用。 为了验证我们的假设，我们将研究RA M β和T细胞与内皮细胞的串扰的贡献。 细胞对骨新生血管形成的影响。随后，为了确定临床前阶段的疗效，TLR 5 Ab治疗 将与RA细胞和临床前模型中目前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 淋巴样细胞，并建立一种新的治疗策略，为RA患者，不响应 目前的治疗。