title: Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis.
abstract: Although interruption of CD40-CD40L interactions via their respective mAbs yields prolonged allograft survival, the relative importance of CD40 or CD40L on donor or host cells remains unknown. Moreover, it is uncertain whether any allospecific tolerance occurring with CD40-CD40L blockade will also prevent allograft arteriopathy, the major long-term limitation to transplantation. Therefore, we performed cardiac transplantations using CD40L-deficient (CD40L-/-) mice to investigate the mechanisms underlying prolonged allograft survival. Without immunosuppression, wild-type (WT) hosts rejected allo-mismatched WT or CD40L-/- heart allografts within 2 wk. Conversely, allografts in CD40L-/- hosts beat vigorously for 12 wk. Anti-CD40 treatment did not induce graft failure in CD40L-/- recipients. Although graft-infiltrating cells were reduced approximately 50% in CD40L-/- hosts, the relative percentages of macrophages and T cell subsets were comparable to WT. IFN-gamma, TNF-alpha, and IL-10 were diminished commensurate with the reduced cellular infiltrate; IL-4 was not detected. CD40L-/- recipients did not develop IgG alloantibodies and showed diminished B7 and CD28 expression on subsets of graft-infiltrating cells. CD40L-/- transplant recipients developed allospecific tolerance to the donor haplotype; second set donor skin grafts engrafted well, whereas third-party skin grafts were vigorously rejected. By MLR, splenocytes from CD40L-/- allograft recipients also demonstrated allo-specific hyporesponsiveness. Nevertheless, allografts in CD40L-/- hosts developed significant graft arteriosclerosis by 8-12 wk posttransplant. Therefore, we propose that early alloresponses, without CD40-CD40L costimulation, induce allospecific tolerance but may trigger allo-independent mechanisms that ultimately result in graft vasculopathy.
authors.affiliation: Departments ofMedicine and Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: U
authors.initials: U
authors.lastname: Schönbeck
authors.forename: F
authors.initials: F
authors.lastname: Mach
authors.forename: P
authors.initials: P
authors.lastname: Libby
authors.forename: R N
authors.initials: RN
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007106:Immune Sera / Q000008:administration & dosage; D007108:Immune Tolerance / Q000235:genetics*; D007111:Immunity, Cellular / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007518:Isoantibodies / Q000096:biosynthesis; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D017252:CD3 Complex; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D016207:Cytokines; D007106:Immune Sera; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D008024:Ligands; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D023201:CD40 Ligand