Date: Sunday, November 5, 2017
Session Title: B Cell Biology and Targets in Autoimmune Disease Poster
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: We have reported that soluble BAFF (sBAFF) robustly increased IL-6 production by peripheral monocytes of patients with primary Sjögren’s syndrome (pSS) and that the expression level of a BAFF receptor (BR3) was significantly elevated in pSS monocytes. In our previous study, we have also demonstrated that the proportion of BR3-positive monocytes to total monocytes was positively and significantly correlated with the serum IgG level of pSS patients. These data collectively suggest that the elevated expression of BR3 on monocytes is involved in IgG overproduction by B cells and that BAFF signaling via BR3 is a possible therapeutic target to treat autoimmune diseases, such as pSS. In addition, we have successfully discovered two pyrrolopryimidine derivatives, which inhibit BAFF binding to BR3, by a high throughput screening of a low molecular weight compound library. These compounds inhibited not only IL-6 and IL-10 production by BAFF-stimulated monocytes, but also IgG production by B cells in vitro co-cultured with monocytes in the presence of sBAFF possibly by impairing differentiation of B cells.Notably, these compounds suppressed the serum level of an anti-dsDNA antibody in autoimmune disease model mice. In this study, we investigate the effects of these compounds on infiltration of B cells into organs of the model mice.
Methods: A pyrrolopryimidine derivative, BIK-13, which inhibits BAFF binding to BR3, was administered intraperitoneally to MRL/lpr mice three times a week at a dose of 0.2 mg/kg for 6 months. Serum levels of an anti-ds DNA antibody, IL-6 and IL-10 were measured by ELISA. The proportion of B cell in peripheral blood of the mice was analyzed by FACS. Infiltration of lymphocytes into organs was analyzed by immunohistochemistry.
Results: Administration of BIK13 to MRL/lpr mice for 16 weeks decreased the serum level of an anti-dsDNA antibody. Moreover, serum levels of IL-6 and IL-10, both of which induce B cell activation, in the mice were concomitantly declined as compared to control mice. Notably, immunohistochemistry revealed that infiltration of B lymphocytes was remarkably suppressed in salivary and lacrimal glands and kidney of the mice. In addition, the proportion of B cells in peripheral blood was also decreased in BIK-13-treated mice as compared to the control mice.
Conclusion: These data collectively suggest that BIK-13, a low molecular weight BR3 antagonist, suppress the B cell activation and resultant infiltration into organs in vivo. Suppression of cytokine production by monocytes may be directly or indirectly involved in the molecular mechanism of the suppression of the B cell activation. The compound may provide a novel therapeutic possibility to treat autoimmune diseases.
To cite this abstract in AMA style:Yoshimoto K, Seki N, Suzuki K, Sugahara K, Takeuchi T. Low Molecular Weight BAFF Receptor Antagonists Restrain Infiltration of B Cells into Organs of Autoimmune Model Mice By Suppressing B Cell Activation [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/low-molecular-weight-baff-receptor-antagonists-restrain-infiltration-of-b-cells-into-organs-of-autoimmune-model-mice-by-suppressing-b-cell-activation/. Accessed August 3, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/low-molecular-weight-baff-receptor-antagonists-restrain-infiltration-of-b-cells-into-organs-of-autoimmune-model-mice-by-suppressing-b-cell-activation/