title: CD40 signaling replaces CD4+ lymphocytes and its blocking prevents chronic rejection of heart transplants.
abstract: Chronic rejection remains the major obstacle to long term survival in heart transplant recipients. The cellular and molecular mechanisms that underlie chronic rejection are not known, and their discovery can form the basis of clinical intervention. Several investigators have suggested that the development of chronic rejection in solid organ transplants is dependent on help mediated by CD4(+) lymphocytes. Importantly, the mechanism through which help is provided has not been fully delineated in transplant rejection. Using a murine heterotopic heart transplant model without immunosuppression, this study defines the functional role of CD4(+) lymphocytes in chronic rejection. In an MHC class II-mismatched model, we demonstrate that chronic rejection was absolutely contingent on the presence of CD4(+) lymphocytes. Importantly, here we report that signaling through CD40 can replace the requirement of CD4(+) lymphocytes, demonstrated by the development of chronic rejection in CD4 knockout recipients treated with a CD40-activating mAb (FGK45). The return of rejection appears to be a CD8(+) lymphocyte-dependent process, noted by the absence of rejection in FGK45-treated recombinase-activated gene knockout (CD4(+) and CD8(+) lymphocyte-deficient) recipients. The CD40 signaling pathway works independently of B7-CD28 costimulation, as indicated by the development of severe chronic rejection in CD28 knockout recipients. Importantly, this study provides evidence that CD40 ligand-targeted therapies may prevent chronic rejection only in strain combinations where CD4(+) lymphocyte help is absolutely required.
authors: Department of Microbiology, Immunology, and Molecular Genetics, Division of Cardiothoracic Surgery, University of California Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
authors: M P
authors: MP
authors: Fischbein
authors: A
authors: A
authors: Ardehali
authors: J
authors: J
authors: Yun
authors: S
authors: S
authors: Schoenberger
authors: H
authors: H
authors: Laks
authors: Y
authors: Y
authors: Irie
authors: P
authors: P
authors: Dempsey
authors: G
authors: G
authors: Cheng
authors: M C
authors: MC
authors: Fishbein
authors: B
authors: B
authors: Bonavida
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000502:physiology; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D003327:Coronary Disease / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology* / Q000503:physiopathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006650:Histocompatibility Testing; D018398:Homeodomain Proteins / Q000235:genetics; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D018398:Homeodomain Proteins; D007106:Immune Sera; D008562:Membrane Glycoproteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D023201:CD40 Ligand