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-γ (IFN-γ), 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-γ-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-γ-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.

Conclusion.

Among the inflammatory cytokines, TNF seems to play a crucial role in the immunopathology of OAD developed after transplantation.