Co-stimulatory modulation in rheumatoid arthritis: the role of (CTLA4-Ig) abatacept.
Associations between rheumatoid arthritis (RA) susceptibility and polymorphism in multiple immunoregulatory genes suggest a role of altered T cell function in the disease. The growing relevance of the oxidative stress in RA synovitis, which results in a number of T cell signalling abnormalities, is reinforced by the demonstration of a direct NO inducing activity through the shared epitope of the HLA class II molecules HLA-DRbeta1, with secondary lymphocytes oxidative damage. Direct T cell/macrophage contact-dependent activation, one of the driving mechanisms of synovitis, is mediated by co-stimulatory molecules as well as cell membrane cytokines and may also result in an impaired suppressive function of T regulatory cells (Treg) in RA joints. The fusion of CTLA4 extracellular binding domain to the Fcgamma1 allows to obtain a soluble CTLA4 receptor, the dimeric recombinant human fusion protein abatacept (CTLA4-Ig). The improved knowledge of the CTLA4-B7 co-stimulation regulatory mechanisms by signals delivered into DCs and Tregs provides multiple potential targets for the abatacept treatment. CTLA4-Ig shows the capacity, either ex vivo or in vivo, to interrupt at multiple steps the ongoing inflammatory and destructive process, and to concur in restoring the immunoregulatory balance in RA.
Fiocco
Ugo
U
Rheumatology Unit, University of Padova, Via Giustiniani 2-35128 Padova, Italy. ugo.fiocco@unipd.it
Sfriso
Paolo
P
Oliviero
Francesca
F
Pagnin
Elisa
E
Scagliori
Elena
E
Campana
Carla
C
Dainese
Serena
S
Cozzi
Luisella
L
Punzi
Leonardo
L
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000628:therapy; D018122:B7-1 Antigen / Q000378:metabolism; D060908:CTLA-4 Antigen; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D018796:Immunoconjugates / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D018716:Molecular Mimicry; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D006684:HLA-DR Antigens; D018796:Immunoconjugates; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D000069594:Abatacept