Selective inhibition of Tfh cells by a small molecule inhibitor abrogates progression of experimental inflammatory arthritis

Abstract

Abstract Background Rheumatoidarthritis (RA) is an inflammatory autoimmune disease characterized by T cell infiltration in the joints and autoantibody production. T follicular helper (Tfh) cells are a unique subset of CD4+ T cells regulating antibody production in B cell follicle. Our previous studies have showed that increased circulating Tfh cells were correlated with anti-CCP antibody titer and disease activity in active RA patients, indicating that Tfh cells may play an important role in RA pathogenesis. Here we investigate the therapeutic potential of a small molecule inhibitor targeting Tfh cells (SMI-Tfh) in mice with collagen-induced arthritis (CIA). Methods CIA was induced in DBA/1 mice by immunization with chicken type II collagen. Following the onset of clinical arthritis, mice were treated with SMI-Tfh (50mg/kg/day) for 10 days. Arthritis progression was monitored daily and recorded by the paw swollenness. Blood, spleen, and affected paws were collected at the end of the study. Tfh cells were examined and defined by CD4+CXCR5+ICOS+via flow cytometry and further confirmed by immunohistochemistry staining in spleen. Results Mice developed arthritis four weeks after immunization with type II collagen. Treatment with SMI-Tfh significantly reduced the disease progression/activity in mice with CIA. SMI-Tfh significantly inhibited the frequency of Tfh cells in spleen (P<0.01), but not the frequency of circulating Tfh cells in CIA mice (P>0.05). Conclusion The small molecule inhibitor SMI-Tfh selectively inhibits Tfh cells and abrogates progression/activity of inflammatory arthritis in CIA mouse model. Treatment with SMI-Tfh in CIA mice provides a potential strategy for joint protection and may be beneficial in RA patients.