title: Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways.
abstract: The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.
authors.affiliation: The Carlos and Marguerite Mason Transplantation Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: E T
authors.initials: ET
authors.lastname: Elwood
authors.forename: D Z
authors.initials: DZ
authors.lastname: Alexander
authors.forename: S C
authors.initials: SC
authors.lastname: Ritchie
authors.forename: R
authors.initials: R
authors.lastname: Hendrix
authors.forename: C
authors.initials: C
authors.lastname: Tucker-Burden
authors.forename: H R
authors.initials: HR
authors.lastname: Cho
authors.forename: A
authors.initials: A
authors.lastname: Aruffo
authors.forename: D
authors.initials: D
authors.lastname: Hollenbaugh
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: K J
authors.initials: KJ
authors.lastname: Winn
authors.forename: T C
authors.initials: TC
authors.lastname: Pearson
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept