Innovative drug discovery for autoimmune diseases aiming at BAFF signaling pathway

Abstract

Abstract Background and Purpose It is well known that BAFF (B cell activating factor) signaling is involved in the pathogenesis of autoimmune diseases. To search for specific inhibitors against BAFF signaling, we have established our original high throughput screening system and discovered a pyrroloprymidine derivative, BIK-13, which inhibits BAFF binding to its receptor, BR3. In this study, we explored the possibility of BIK-13 as a drug to treat autoimmune diseases. Methods Human PBMC were stimulated in vitro with a mixture of BAFF, IL-21, and anti-IgM and anti-CD40 antibodies in the presence of BIK-13. Differentiation of B cells and the expression level of Activation-induced cytidine deaminase (AID) in the cells were analyzed by FACS and qPCR, respectively. The amounts of IL-6, IL-10 and IgG in the culture supernatants were measured by ELISA. Serum levels of an anti-dsDNA antibody, IL-6 and IL-10 in BIK-13-treated autoimmune model mice, MRL/lpr, were measured by ELISA. The proportion of B cells among splenocytes and infiltration of lymphocytes into organs of the mice were analyzed by FACS and immunohistochemistry, respectively. Results In vitro experiments revealed that BIK-13 suppressed 1) differentiation of B cells, 2) AID expression and 3) IL-6, IL-10 and IgG production in a dose dependent manner. BIK-13 decreased the serum levels of an anti-dsDNA antibody, IL-6 and IL-10 in MRL/lpr mice. Notably, infiltration of B cells into lacrimal glands and the proportion of B cells among splenocytes were remarkably suppressed in BIK-13-treated mice. Conclusion Our data collectively suggest that BIK-13, a low molecular weight BAFF-signaling inhibitor, is a promising drug candidate for autoimmune diseases by suppressing B cell activation.