Interference with cyclophosphamide-induced skin allograft tolerance by cyclosporin A.
In a murine strain combination identical in H-2 Ag but disparate in minor histocompatibility (H) Ag consisting of C3H/He (C3H; H-2k, Mls-1b) mice as recipients and AKR/J (AKR; H-2k, Mls-1a) mice as donors, a permanent skin allograft tolerance can be achieved by the cyclophosphamide (CP)-induced tolerance system that consists of i.v. injection of donor spleen cells (day -2) and i.p. injection of CP 2 days later (day 0). Such permanent take of allografts in CP-induced tolerant mice was interfered with by intramuscular injection of cyclosporin A (CsA) from day -5 to day -1 and their grafts were rejected by 21 days after grafting. Mls-1a-reactive CD4+V beta 6+ T cells in the periphery, as the indicator to follow the kinetics of donor-reactive T cells, increased on day 0 and day 3 in the C3H mice treated with AKR spleen cells alone, whereas they disappeared rapidly from day 0 to day 3 in CP-induced tolerant mice. When CsA capable of interfering with IL-2 production and T cell proliferation was administered before CP treatment in CP-induced tolerance system, the number of CD4+V beta 6+ T cells in periphery did not increase on day 0 and 3, but increased on day 7 in contrast to the decreased number of those in CP-induced tolerant mice. On day 7, MLR against donor cells was decreased in CP-induced tolerant mice, but maintained in CsA-interfered tolerant mice. These result may indicate that the destruction of donor-Ag-stimulated, proliferating T cells by CP is interfered with by CsA, probably because CsA inhibits the proliferation of donor-reactive T cells at the time of CP treatment. Furthermore, these results also implicate that the protocol for immunosuppression with CsA and antimetabolites has to be designed carefully in clinical transplantation.
Nomoto
K
K
Department of Immunology, Kyushu University, Fukuoka, Japan.
Eto
M
M
Yanaga
K
K
Nishimura
Y
Y
Maeda
T
T
Nomoto
K
K
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D003520:Cyclophosphamide / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D006085:Graft Survival / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous
D015704:CD4 Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016572:Cyclosporine; D003520:Cyclophosphamide