title: Prevention of obliterative airway disease in HLA-A2-transgenic tracheal allografts by neutralization of tumor necrosis factor.
abstract: BACKGROUND
  Inflammatory cytokines play an important role in the development of experimental obliterative airway disease (OAD) after transplantation. To further determine the immunologic mechanisms associated with OAD development, we used a murine tracheal transplant model in which a single mismatched HLA-A2-transgenic molecule is indirectly recognized by the recipient CD4+ T cells and then determined whether neutralization of several inflammatory cytokines affected the development of OAD.
  
  
  METHODS
  Tracheas from HLA-A2+ C57BL/6 mice were heterotopically transplanted into C57BL/6 mice. Recipients were treated with neutralizing antibodies against tumor necrosis factor (TNF), interferon-gamma (IFN-gamma), or interleukin-1 (IL-1). Allograft histology as well as anti-HLA-A2 antibody development and T cell proliferative responses were determined at days +5, +15, +28, and +60.
  
  
  RESULTS
  Allografts in untreated and anti-IFN-gamma-treated recipients demonstrated full development of OAD by day +28. Allografts in anti-TNF-treated recipients showed no evidence of OAD, even at day +60. Allografts in anti-IL-1-treated recipients showed airway epithelium changes by day +28 but minimal evidence of OAD by day +60. Spleen cells from untreated and anti-IFN-gamma-treated recipients showed significantly higher proliferative responses to HLA-A2+ cells, compared with syngeneic recipients (negative controls). In contrast, anti-TNF and anti-IL-1-treated recipients showed significantly lower proliferative responses to HLA-A2+ cells, compared with untreated recipients. Development of anti-HLA-A2 antibodies was detected in all recipients by day +15, with the exception of those treated with anti-TNF.
  
  
  CONCLUSIONS
  Among the inflammatory cytokines, TNF seems to play a crucial role in the immunopathology of OAD developed after transplantation.
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Jaramillo
authors.forename: K C
authors.initials: KC
authors.lastname: Lu
authors.forename: T
authors.initials: T
authors.lastname: Higuchi
authors.forename: Z
authors.initials: Z
authors.lastname: Kaleem
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000402:Airway Obstruction / Q000517:prevention & control*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015789:HLA-A2 Antigen / Q000235:genetics*; D007371:Interferon-gamma / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D007518:Isoantibodies / Q000097:blood; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009500:Neutralization Tests; D014132:Trachea / Q000637:transplantation*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000473:pathology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015789:HLA-A2 Antigen; D007375:Interleukin-1; D007518:Isoantibodies; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma