Allograft tolerance induced by cyclophosphamide without prior inoculation of donor cells - immune suppression and redirection

Objectives To determine the possibility and cellular mechanism of inducing allograft tolerance by multiple injection of a lower dose of cyclophosphami de without prior infusion of donor cells. Methods and results: Heterotopic heart grafts were performed in MHC mismatched strain combinations (C57/B6 v s. BALB/c). Cyclophosphamide (40 mg/kg) was given intravenously on days 0, 2, 4 and 7 without prior infusion of donor cells. Long-term (> 100 days) al lograft survival with normal histology was achieved. The long-term survivor s accepted the donor skin grafts, but rejected the third-party skin grafts. Cyclophosphamide treatment initially led to profound lymphocytopenia, inhi bition of spontaneous blastogenesis and low levels of lymphocyte proliferat ion response to both donor and third-party antigens. Ultimately, donor-spec ific tolerance occurred demonstrated by normal levels of peripheral lymphoc ytes, spontaneous blastogenesis and lymphocyte proliferation response to th ird-parry antigens, and low levels of lymphocyte proliferation response to donor antigen. A switch of cytokines from IFN gamma dominant to IL-4 domina nt, a low level of IgM and a high level of IgG1 were found in tolerant mice . Conclusions: Allograft tolerance can be induced by a short course of cycl ophosphamide without prior donor cell inoculation. Tolerance induced is cha racterized initially by non-specific immunosuppression, which progresses to donor-specific hyporesponsiveness associated with the development of a Th2 dominant cytokine response. (C) 2000 Elsevier Science B.V. All rights rese rved.