title: Selective elimination of pathogenic synovial fluid T-cells from rheumatoid arthritis and juvenile idiopathic arthritis by targeted activation of Fas-apoptotic signaling.
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.
authors.affiliation: Department of Surgery, Surgical Research Laboratory, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.forename: Wineke
authors.initials: W
authors.lastname: Armbrust
authors.forename: E
authors.initials: E
authors.lastname: Brouwers
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019011:Antigens, CD7 / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D053222:Fas Ligand Protein / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
chemical_list: D019011:Antigens, CD7; D017252:CD3 Complex; D053222:Fas Ligand Protein; D053245:RANK Ligand; D011993:Recombinant Fusion Proteins; C505688:TNFSF11 protein, human; D019014:fas Receptor