Discovering a novel therapy for RA patients

发现一种治疗 RA 患者的新疗法

• 批准号: 9889790
• 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/9889790
• 关键词: Affect; African American; Agonist; Anti-Tumor Necrosis Factor Therapy; Antibodies; Antibody Therapy; Arthritis; Autoimmune Diseases; Autoimmune Process; Binding; 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; Hispanics; 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; 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; 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.

类风湿关节炎（RA）是最常见的自身免疫性疾病，影响着全球250万人