Different kinetics of obliterative airway disease development in heterotopic murine tracheal allografts induced by CD4+ and CD8+ T cells1

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Abstract
Background. Both T and B cells have been shown to be implicated in the pathogenesis of bronchiolitis obliterans syndrome, which is considered to represent chronic lung allograft rejection. However, the relative contributions of T cells and alloantibodies in the pathogenesis of the disease are still unknown. In this study, we used an heterotopic murine tracheal transplantation model to determine the contribution of these components of the immune system in the pathogenesis of posttransplant obliterative airway disease (OAD). Methods. Tracheal allografts from BALB/c and HLA-A2-transgenic (HLA-A2+) mice were heterotopically transplanted into C57BL/6, CD4-knockout (KO), CD8-KO, Ig-KO, and Rag1-KO mice. In additional experiments, recipient mice were pretreated with depleting antibodies against CD4+, CD8+, and NK1.1+ cells. Development of OAD was determined by histopathology at days 10, 30, 60, 90, and 180 after transplantation. Results. HLA-A2+ allografts transplanted into C57BL/6, CD8-KO, and Ig-KO mice demonstrated OAD lesions by day 30. In contrast, allografts transplanted into CD4-KO mice showed no OAD lesions at day 30, partial OAD development by days 60 and 90, and complete OAD development by day 180. No OAD development was observed in allografts transplanted into Rag1-KO mice. Treatment with anti-NK1.1 antibody did not show any effect on posttransplant OAD development. In contrast, anti-CD4+ or anti-CD8+ antibody treatments partially reduced the OAD histopathology and combined anti-CD4/CD8 antibody treatment further abrogated the histopathology of the disease. Conclusion. These results show that both CD4+ and CD8+ T cells have a role in the pathogenesis of OAD and that natural killer cells and alloantibodies are not necessary for the development of this disease.
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