CTLA4-FasL fusion product suppresses proliferation of fibroblast-like synoviocytes and progression of adjuvant-induced arthritis in rats

Fibroblast-like synoviocytes (FLSs) contribute significantly to the pathogenesis of Rheumatoid arthritis (RA). Through introducing apoptosis inducer FasL to suppress the proliferation of arthritic FLSs may provide an efficient approach for treatment of RA. CTLA4-FasL, a fusion product integrating two inhibitory elements of CTLA4 (which can induce T cell anergy through blocking costimulatory signal) and FasL (which may upregulate Fas-mediated apoptosis in inflammatory synoviocytes) into one molecule, might be a desirable engineered derivative of soluble FasL which exerts severe side effects and poor activities. In present study, we investigated the possible effect of CTLA4-FasL protein on suppressing the proliferation of inflammatory FLSs and inflammation in experimental model of RA. The purified CTLA4-FasL protein exerted a significant proliferation-inhibition activity to activated arthritic FLSs through both unbounded free and membrane-anchorage manners. CTLA4-FasL gene delivery by recombinant adeno-associated virus (rAAV) vector in joint, provided more powerfully preventive effects than mature FasL on rat adjuvant-induced arthritis (AIA) as reflected in clinical signs and typically histological characters. Treatment with rAAV.CTLA4-FasL also significantly decreased the levels of key proinflammatory cytokines in AIA joints. Our observations indicate that CTLA4-FasL protein represents a significantly suppressive effect on inflammatory FLSs' proliferation and CTLA4-FasL gene transfer profoundly suppresses AIA, implicating potential application for treatment of RA by local joint delivery of CTLA4-FasL. (c) 2012 Elsevier Ltd. All rights reserved.