title: Blocking CD40 - CD154 and CD80/CD86 - CD28 interactions during primary allogeneic stimulation results in T cell anergy and high IL-10 production.
abstract: Although CD28 triggering provides an important co-stimulatory signal to T cells, blocking the CD80/CD86 - CD28 interaction with CTLA-4lg fusion protein is not sufficient for tolerance induction in vivo or in vitro. According to more recent data, interruption of the CD40 - CD154 interaction might complement the effect of CTLA-4lg and induce graft acceptance. We studied the effects of a blocking anti-CD40 monoclonal antibody (mAb) and/or blocking anti-CD80/anti-CD86 mAb in cultures of human peripheral blood mononuclear cells (PBMC) stimulated with allogeneic PBMC. T cells activated by alloantigens in the presence of anti-CD80, anti-CD86 and anti-CD40 entered a state of alloantigen-specific non-responsiveness as evidenced upon restimulation by lack of proliferation, cytotoxic activity, and IL-2, IL-5 and IL-13 production. IFN-gamma production during restimulation was less than in the control cultures, while the production of IL-10 was enhanced. Addition of recombinant IL-2 during the restimulation rescued alloantigen-specific activity. We conclude that the simultaneous blocking of the CD40 - CD154 and CD80/CD86 - CD28 interaction during allogeneic T cell activation induces T cell anergy. Since anergic cells induced by this treatment still produce high levels of IL-10, the latter could contribute to modulation of antigen-presenting cell activity and to bystander suppression of residual reactive T cells.
authors.affiliation: Laboratory of Experimental Immunology, Catholic University of Leuven, Leuven, Belgium. Stefaan.VanGool@uz.kuleuven.ac.be
authors.forename: S W
authors.initials: SW
authors.lastname: Van Gool
authors.forename: J
authors.initials: J
authors.lastname: Vermeiren
authors.forename: K
authors.initials: K
authors.lastname: Rafiq
authors.forename: K
authors.initials: K
authors.lastname: Lorr
authors.forename: M
authors.initials: M
authors.lastname: de Boer
authors.forename: J L
authors.initials: JL
authors.lastname: Ceuppens
mesh_terms: D000069594:Abatacept; D000328:Adult; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D017635:Clonal Anergy; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D018796:Immunoconjugates; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis*; D007378:Interleukins / Q000096:biosynthesis; D007519:Isoantigens; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007378:Interleukins; D007519:Isoantigens; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10; D023201:CD40 Ligand; D000069594:Abatacept