alexa Selective elimination of pathogenic synovial fluid T-cells from rheumatoid arthritis and juvenile idiopathic arthritis by targeted activation of Fas-apoptotic signaling.


Journal of Clinical & Cellular Immunology

Author(s): Bremer E, Abdulahad WH, de Bruyn M, Samplonius DF, Kallenberg CG,

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Abstract In Rheumatoid Arthritis (RA) and Juvenile Idiopathic Arthritis (JIA) elimination of autoreactive T-cells by FasL/Fas-mediated Activation-Induced Cell Death (AICD) appears to be inhibited resulting in the perpetuation of the inflammatory response and concomitant progressive tissue destruction. Here, we report on a novel strategy that aims to overcome the local inhibition of AICD by using rationally designed recombinant fusion proteins in which sFasL is genetically fused to a T-cell selective targeting domain. The series included sFasL fusion proteins with engineered binding specificity for various T-cell surface-expressed proteins including CD7, CD28, RANKL and CD40L. The proposed mode of action is that selective binding of a given sFasL fusion protein results in its accretion at the cell surface of T-cells only, displaying a surplus of sFasL that is available to reactivate AICD in pathogenic synovial T-cells. Of the series of T-cell targeting FasL fusion proteins a CD7-targeted fusion protein, designated scFvCD7:sFasL, proved to be the most potent, with significant pro-apoptotic activity towards synovial fluid T-cells in all patient samples tested (RA; n=22: JIA; n=6). Treatment with scFvCD7:sFasL induced up to 80\% apoptosis in CD3-positive synovial T-cells. Importantly, scFvCD7:sFasL potently activated Fas-signaling in synovial T(H1)-cells as well as synovial T(reg) cells, but not in synovial T(H2) cells. These findings indicate that scFvCD7:sFasL may be of therapeutic value for the selective elimination of pathogenic synovial T-cells of the T(H1) subtype in both RA and JIA. Copyright © 2011 Elsevier B.V. All rights reserved. This article was published in Immunol Lett and referenced in Journal of Clinical & Cellular Immunology

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