COMBINATION OF CTLA4IGG AND FTY720 SUPPRESSES DEVELOPMENT OF OBLITERATIVE BRONCHIOLITIS AND RESPIRATORY EPITHELIAL INJURY IN A MURINE HETEROTOPIC AIRWAY MODEL

Abstract

250 Combination of CTLA4IgG and FTY720 suppress development of Background: Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologically by fibroproliferation within small airways. The pathogenesis of OB is thought to involve chronic allograft rejection process, and therapy frequently includes immunosuppression. Recently Hertz and collogue have developed a model that reproduces the pathologic lesion of OB and allows study of interventions designed to limit airway fibrosis. In this model, heterotopic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the airway lumen, changes not seen in heterotopic isografts. CTLA4IgG inhibits activation and proliferation of T lymphocytes through the suppression of CD28-B7 pathway that is the best-characterized costimulatory signal. It has been reported that CTLA4IgG induces T cell anergy and inhibits allo-immune responses in organ transplantation. While, FTY720 is a recently discovered compound derived from the fungus. Isaria sinclairii and induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing. Additionally. FTY720 prolongs allograft survival in several organ transplantation models. Purpose: We previously demonstrated that the development of fibroproliferation and airway epithelial cell injury in allograft were completely inhibited in nude mouse recipients, indicating that T cells played an important role in fibromuscular hyperplasia and respiratory epithelial injury in a murine heterotopic air way model. We hypothesized that combination therapy of CTLA4IgG and FTY720 would induce T cell anergy more efficiently in vivo. Methods: To test this hypothesis, murine tracheas were transplanted heterotopically into allo-matched and allo-mismatched recipients, and then treated with varying doses (0.2 or 0.5 mg/time i.p.) of CTLA4IgG and (1 or 5 mg/kg i.p.) of FTY720. Controls included allografts and isografts not treated with both regents. After 35 days, tracheas were harvested and examined histologically. Results: Both CTLA4IgG and FTY720 markedly reduced the development of fibroproliferation in allografts, but did not reduce airway epithelial cell injury, respectively (Table 1). On the other hand, combination therapy of CTLA4IgG and FTY720 blocked not only the development of fibroproliferation in allograft but also the airway epithelial cell injury (Table 1). Conclusions: Thus, we concluded that a new combination therapy using CTLA4IgG and FTY720 may be very useful for the suppression of T cell-mediated chronic rejection after lung transplantation. We believe that this therapy could be useful not only for prevention of chronic rejection model but also for acute rejection ones such as renal, heart, small bowel, and liver transplantations.Table 1