Modefication of the drug-induced tolerance induction to large animals

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Post-transplant cardiac allograft vasculopathy (CAV) is a key manifestation of chronic rejection in heart transplant recipients and impairs long-term graft outcome. In the present study, we have investigated whether CAB can be prevented by the treatment of cyclophosphamide (CP)-induced tolerance in a murine CAV model of H-2 matched AKR (H-2ィイD2kィエD2 ; Thy1.1, M1s-1ィイD2aィエD2) into C3H (H-2ィイD2kィエD2 ; Thy1.1, M1s-1ィイD2bィエD2) mice. When C3H mice were grafted with H-2 matched AKR heart grafts (HG), most of AKR HG survived over 100 days, but all were rejected within 260 days after grafting. CAV developed in all AKR HG. When C3H mice were primed I.e. with1x10ィイD28ィエD2 AKR(H-2k_) spleen cells (SC) and treated I.p. with 200mg/kg CP, the survival of AKR hearts was prolonged permanently in tolerogen-specific fashion, as observed in that of AKR skins. By this treatment, both minimal degree of mixed chimerism and clonal destruction of M1s-1ィイD2aィエD2-reactive CD4+Vβ6+T cells in the periphery were o … More bserved. Furthermore, post-transplant CAV did not develop in the grafted AKR hearts. When AKR SC and 100mg/kg CP were used as the conditioning, AKR HG were accepted permanently, but survival of AKR skin grafts was mildly prolonged. The clonal destruction of CD4+Vβ6+T cells was induced in the periphery. A minimal degree of mixed chimerism was detective at 4 weeks after AKR SC and 100mg/kg CP treatment, but hardly became detectable at 20 weeks. In the AKR HG of C3H mice treated with AKR SC and 100mg/kg CP, post-transplant CAV did not develop, either. Second set skin grafts from donor AKR mice survived in a tolerogen-specific fashion over 100 days in 10/10 C3H mice treated with AKR SC and 200mg/kg CP and accepting AKR HG over 200 days, and 8/10 C3H mice treated with AKR SC and 100 mg CP and accepting AKR HG over 200 days. In order to further elucidate the nature of tolerance induced with AKR SC and CP, PCR assay was performed. Neither Th1 (IL-2, g-IFN) nor Th2 (IL-4, IL-10) cytokines were accumulated at 4 weeks post-heart grafting in the AKR HG of tolerant C3H mice treated with both AKR SC and 200mg/kg CP and AKR SC and 100mg/kg CP.These results indicate that the suboptimal conditioning (SC+100mg/kg CP) of CP-induced tolerance with 1x10ィイD28ィエD2 SC and 100 mg/kg CP can permit heart allograft without the development of CAV or accumulation of mRNAs for Th1 or Th2 cytokines. Furthermore, the induction of skin allograft tolerance is more difficult than the prevention of post-transplant CAV. Less