title: Marked mitigation of transplant vascular sclerosis in FasLgld (CD95L) mutant recipients. The role of alloantibodies in the development of chronic rejection.
abstract: BACKGROUND
  In the acute rejection of allografts, the interaction between Fas (CD95) and its ligand (FasL; CD95L) has been shown to be involved in mediating apoptotic cell death. The role, however, of these molecules in the pathogenesis of transplant vascular sclerosis is as yet undetermined. The present study was therefore designed to address this issue.
  
  
  METHODS
  C3H/HEJ FasLgld (FasL-; H2k) spontaneously mutant mice were used either as donors or recipients of aortic allografts; wild-type C57B1/6 (B6; H2b) were used as corresponding recipients or donors (n=6/group), respectively. Controls included aortas transplanted across appropriate allogeneic and syngeneic strain combinations. For histopathological evaluations, the grafts were harvested at day 40 after transplantation, at which time, splenocytes and sera were also obtained for mixed leukocyte reaction and complement-mediated microcytotoxicity assays, respectively.
  
  
  RESULTS
  Similar to aortas obtained from allogeneic controls, allografts harvested from FasL- -->B6 recipients had morphological evidence of chronic rejection characterized by circumferential intimal thickening with partial disruption of the elastic membranes. Correspondingly, heightened antidonor cellular reactivity was also witnessed in these recipients. On the contrary, B6 allografts harvested from the majority of C3H-->FasL- recipients exhibited marked preservation of aortic morphology. Although these recipients had diminished antidonor cellular proliferation, the titers of alloantibodies were markedly elevated.
  
  
  CONCLUSIONS
  The presence of FasL-expressing functional cytotoxic T cells is required for the pathogenesis of transplant vascular sclerosis. The significant reduction and/or absence of chronic rejection with the concomitant retention of antidonor humoral response in C3H FasL- recipients of B6 aortas prompt us to suggest that perhaps posttransplantation vasculopathy is initiated by cell-mediated cytotoxicity with its perpetuation facilitated by alloantibodies.
authors.affiliation: Thomas E. Starzl Transplantation Institute and the Department of Pathology, University of Pittsburgh Medical Center, Pennsylvania 15213, USA.
authors.forename: V
authors.initials: V
authors.lastname: Subbotin
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: A
authors.initials: A
authors.lastname: Aitouche
authors.forename: A
authors.initials: A
authors.lastname: Salam
authors.forename: L A
authors.initials: LA
authors.lastname: Valdivia
authors.forename: J J
authors.initials: JJ
authors.lastname: Fung
authors.forename: T E
authors.initials: TE
authors.lastname: Starzl
authors.forename: A S
authors.initials: AS
authors.lastname: Rao
mesh_terms: D000818:Animals; D001011:Aorta / Q000637:transplantation*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000502:physiology; D008024:Ligands; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D017354:Point Mutation; D019014:fas Receptor / Q000502:physiology
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007518:Isoantibodies; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor