Allograft tolerance induced by cyclophosphamide without prior inoculation of donor cells--immune suppression and redirection.
OBJECTIVE
To determine the possibility and cellular mechanism of inducing allograft tolerance by multiple injection of a lower dose of cyclophosphamide without prior infusion of donor cells.


RESULTS
Heterotopic heart grafts were performed in MHC mismatched strain combinations (C57/B6 vs. 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) allograft survival with normal histology was achieved. The long-term survivors accepted the donor skin grafts, but rejected the third-party skin grafts. Cyclophosphamide treatment initially led to profound lymphocytopenia, inhibition of spontaneous blastogenesis and low levels of lymphocyte proliferation response to both donor and third-party antigens. Ultimately, donor-specific tolerance occurred demonstrated by normal levels of peripheral lymphocytes, spontaneous blastogenesis and lymphocyte proliferation response to third-party antigens, and low levels of lymphocyte proliferation response to donor antigen. A switch of cytokines from IFNgamma dominant to IL-4 dominant, 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 cyclophosphamide without prior donor cell inoculation. Tolerance induced is characterized initially by non-specific immunosuppression, which progresses to donor-specific hyporesponsiveness associated with the development of a Th2 dominant cytokine response.
Gao
Z H
ZH
Department of Surgery, The University of Western Ontario, London, Canada.
Lazarovits
A I
AI
Wang
J
J
Xing
J
J
Garcia
B
B
Kellersmann
R
R
Kelvin
D
D
Zhong
R
R
D000818:Animals; D003520:Cyclophosphamide / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide