title: Alloantigen-driven T cell death mediated by Fas ligand and tumor necrosis factor-alpha is not essential for the induction of allograft acceptance.
abstract: BACKGROUND
  Fas ligand (FasL)-Fas and tumor necrosis factor alpha (TNFalpha)-tumor necrosis factor receptor (TNFR) interactions regulate immune responses and contribute to self-tolerance by mediating antigen-driven T cell apoptosis. It is not known whether FasL and TNFalpha, expressed by the recipient's lymphoid or nonlymphoid cells, are essential for the apoptosis of alloreactive T lymphocytes and the induction of allograft acceptance.
  
  
  METHODS
  We compared the survival of fully allogeneic vascularized cardiac allografts between wild-type (wt) and FasL-mutant (gld) recipient mice. In addition, we studied cardiac allograft survival in gld mice injected with TNFalpha-neutralizing antibody. Allograft acceptance (graft survival >100 days) was induced by treating the recipients with CTLA4Ig, a recombinant fusion protein that blocks B7-CD28 T cell costimulation. In vivo alloantigen-driven apoptosis of mature CD4+ and CD8+ T lymphocytes was analyzed in mice repeatedly stimulated with allogeneic splenocytes.
  
  
  RESULTS
  We found that CTLA4Ig induces 100% long-term acceptance of cardiac allografts in wt and gld mice. Similarly, CTLA4Ig induced 100% allograft acceptance in gld recipients injected with TNFalpha-neutralizing antibody. In vivo alloantigen-driven apoptosis of mature CD4+ and CD8+ T cells was significantly reduced in gld mice and in wt mice treated with anti-TNFalpha antibody. However, neutralizing TNFalpha activity in gld mice failed to abrogate alloantigen-driven T cell apoptosis.
  
  
  CONCLUSIONS
  These data indicate that: (1) FasL and TNFalpha expression are not obligatory for the induction of long-term allograft acceptance by CTLA4Ig and (2) FasL- and TNFalpha-independent death pathways contribute to alloantigen-driven T cell apoptosis.
authors.affiliation: The Carlos and Marguerite Mason Transplantation Research Center, Department of Medicine, Emory University and the Medical and Research Services, Veterans Affairs Medical Center, Atlanta, GA 30033, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Wagener
authors.forename: B T
authors.initials: BT
authors.lastname: Konieczny
authors.forename: Z
authors.initials: Z
authors.lastname: Dai
authors.forename: G H
authors.initials: GH
authors.lastname: Ring
authors.forename: F G
authors.initials: FG
authors.lastname: Lakkis
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000209:etiology; D006085:Graft Survival / Q000502:physiology*; D007519:Isoantigens / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000502:physiology*; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007519:Isoantigens; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha