title: Prolonged murine cardiac allograft acceptance: characteristics of persistent active alloimmunity after treatment with gallium nitrate versus anti-CD4 monoclonal antibody.
abstract: We have treated DBA/2-->C57BL/6 murine cardiac allograft recipients with anti-CD4 monoclonal antibody or with gallium nitrate to promote long-term (>60 days) allograft survival. Within this period, all grafts developed histologic evidence of ongoing vascular and parenchymal tissue remodeling, including interstitial fibrosis and neointimal hyperplasia, which are characteristic of chronic allograft rejection. To evaluate residual alloimmunity associated with the pharmacologic avoidance of acute graft rejection and the development of chronic tissue remodeling, we subjected these graft recipients to a battery of histologic and immunologic tests. Similar test results were obtained for graft recipients treated with either of the two immunosuppressive agents. All long-surviving allografts displayed histologic evidence of ongoing microvascular endothelial activation and interstitial leukocytic infiltration. Reverse transcriptase-polymerase chain reaction analyses demonstrated intragraft expression of mRNAs for interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor, interferon-gamma, and transforming growth factor-beta. All recipients had limiting dilution analysis-detectable, graft-reactive cytolytic T lymphocytes and helper T lymphocytes in their spleens and grafts, and all produced high titers of graft-reactive alloantibodies. In general, these observations indicate that (1) a similar immune status is achieved in long-surviving allografts and their recipients when either anti-CD4 monoclonal antibody or gallium nitrate was used for antirejection therapy, (2) this immune status is characterized by continuous, long-term inflammatory and immune processes that are qualitatively similar to those observed during acute allograft rejection, and (3) no specific immune responses developed selectively in long-term graft recipients to account for the avoidance of acute graft rejection or the development of chronic tissue remodeling in the graft.
authors.affiliation: The Ohio State University College of Medicine, Department of Surgery, Columbus 43210, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Orosz
authors.forename: E
authors.initials: E
authors.lastname: Wakely
authors.forename: D D
authors.initials: DD
authors.lastname: Sedmak
authors.forename: S D
authors.initials: SD
authors.lastname: Bergese
authors.forename: A M
authors.initials: AM
authors.lastname: VanBuskirk
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D002452:Cell Count; D016207:Cytokines / Q000235:genetics; D005260:Female; D005708:Gallium / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000032:analysis; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D013154:Spleen / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology; D014184:Transplantation, Homologous / Q000473:pathology; D014185:Transplantation, Isogeneic / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D012333:RNA, Messenger; D005708:Gallium; C027235:gallium nitrate