IC87114, a Selective Inhibitor of PI3Kδ Suppresses Joint Inflammation and Bone Erosion in Collagen-Induced Arthritis in Rat (50.14)

Abstract

Abstract PI3Kδ plays an essential role in antigen-receptor signaling, proliferation, activation and function of lymphocytes. Mice deficient in PI3Kδ activity show substantial reduction in immunoglobulin levels, partial impairment in chemoattractant-induced neutrophil migration as well as defects in signaling and function of macrophages. Collagen-induced arthritis (CIA), a commonly used model for studying antirheumatic drugs, requires participation of both B and T cells to initiate disease and reproduces many of the pathogenic mechanisms detected in human rheumatoid arthritis. In this study, we have investigated the ability of IC87114, a selective PI3Kδ inhibitor, to reverse the rheumatoid arthritic like state in the CIA model of arthritis. Clinical arthritis was initiated by immunizing animals with collagen followed by a booster dose on day 7. IC87114 or control treatment was initiated when at least one hind paw was significantly inflamed and continued for an 18-day treatment course. IC87114-treatment of arthritic rats reduced the progression and severity of clinical arthritis that was evident within 6 days after initiation of therapy. IC87114-treatment significantly reduced the level of anti-collagen antibodies. Arthritic rats treated with IC87114 had significantly lower radiographic scores compared with control, indicating that treatment with IC87114 was effective in protecting bone integrity. Histopathological evaluation demonstrated that IC87114 was effective in reducing the histological changes induced by rheumatoid arthritis. The effect of IC87114-treatment on these parameters together suggests a therapeutic potential for PI3Kδ-selective compounds to ameliorate rheumatoid arthritis.