Abstract
Sphingosine-1-phosphate receptor subtype 1 (S1P1) is essential for lymphocyte egress from lymphoid organs into systemic circulation and provides a well-defined drug target for autoimmune disorders. IMMH001, also called SYL930, is a specific S1P1/S1P4/S1P5 modulator. Here, we investigated the potential therapeutic effect of IMMH001 on rheumatoid arthritis (RA). IMMH001 rendered periphery blood lymphocytes insensitive to the egress signal from secondary lymphoid organs. Importantly, in both rat adjuvant-induced arthritis and collagen-induced arthritis models, IMMH001 treatment significantly inhibited the progression of RA and RA-associated histological changes in the joints of Sprague-Dawley rats, including hind paw swelling and arthritic index, and thus reduced the pathological score. Furthermore, IMMH001 markedly decreased proinflammatory cytokine and chemokine release from the damaged joints. These data demonstrated that IMMH001 is a promising drug candidate for RA treatment.
Highlights
Rheumatoid arthritis (RA) is a severe lifelong autoimmune disease of the synovial joint tissue, characterized by chronic synovial inflammatory cell infiltration causing cartilage degradation and joint destruction (Oliver and Silman, 2006; Helmick et al, 2008)
Infiltrated cells including granulocytes, monocytes/ macrophages, natural killer (NK) cells, B cells, and especially T cells have been implicated in the pathogenesis of RA by producing many chemokines and proinflammatory cytokines (Drexler et al, 2008; Mellado et al, 2015, Wehr et al, 2018; Yap et al, 2018)
The roles of these inflammatory cells is poorly understood, blocking or inhibiting these cells that secrete proinflammatory cytokines relieves the symptoms of RA (Bullock et al, 2018; Mahajan and Mikuls, 2018)
Summary
Rheumatoid arthritis (RA) is a severe lifelong autoimmune disease of the synovial joint tissue, characterized by chronic synovial inflammatory cell infiltration causing cartilage degradation and joint destruction (Oliver and Silman, 2006; Helmick et al, 2008). Patients are usually administered long-term disease-modifying anti-rheumatic drugs, such as methotrexate (MTX) (Yap et al, 2018). Many immune cells, such as T cells, B cells, and macrophages, play crucial roles in the pathogenesis of RA via stimulating proinflammatory cytokine and chemokine release (Silverman and Carson, 2003; Drexler et al, 2008; Iwamoto et al, 2008; Wang et al, 2011; Mellado et al, 2015; Sun et al, 2018; Wehr et al, 2018; Yap et al, 2018); targeting immune cells or proinflammatory cytokines is beneficial for RA patients (Asquith et al, 2015; Bullock et al, 2018; Littlejohn and Monrad, 2018; Mahajan and Mikuls, 2018; Zhao et al, 2018).
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