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FRACTIONATED DOSING OF CYCLOPHOSPHAMIDE FOR ESTABLISHING LONG-LASTING SKIN ALLOGRAFT SURVIVAL, STABLE MIXED CHIMERISM, AND INTRATHYMIC CLONAL DELETION IN MICE PRIMED WITH ALLOGENEIC SPLEEN CELLS1

1997; Wolters Kluwer; Volume: 63; Issue: 11 Linguagem: Inglês

10.1097/00007890-199706150-00022

1534-6080

Qiwei Zhang, Hisanori Mayumi, Masayoshi Umesue, Yukihiro Tomita, Kikuo Nomoto, Hisataka Yasui,

Tissue Engineering and Regenerative Medicine

Background. Injection of allo-spleen cells (SC) followed by a single dose of cyclophosphamide (CP) can induce tolerance of tumor and/or skin allografts in mice. To minimize the damage caused by CP, fractionation of CP that can establish long-lasting skin graft survival, stable mixed chimerism, and intrathymic clonal deletion in the host was investigated in the present study. Methods. Allo-SC (108) were given intravenously on day 0. CP at 200 mg/kg was given intraperitoneally on day 2 in a single dose (CP 200×1 group). CP at 100, 66, 50, 40, and 33 mg/kg was given daily from day 1 through days 2, 3, 4, 5 and 6, respectively, in the fractionated doses (CP 100×2, 66×3, 50×4, 40×5, and 33×6 groups; total dose=200 mg/kg). Allografting was performed on day 14. Results. In a fully allogeneic combination of C57BL/6 (H2b)→AKR (H2k, Mls-1a), an EL-4 tumor (H2b) was specifically accepted to kill the AKR mice in all of the SC+CP 200×1, 100×2, 66×3, 50×4, 40×5, and 33×6 group (n=6), but C57BL/6 skin graft survival was not prolonged in any of the tumor-tolerant groups. In an H2-identical combination of AKR→C3H (H2k, Mls-1b), AKR skin graft survival was prolonged remarkably (80-90 days) in the SC+CP 200×1, 100×2, and 66×3 groups (n=5-11), but was prolonged moderately (20-60 days) in the SC+CP 50×4 and 40×5 groups. In both of the SC+CP 200×1 and 66×3 groups in the AKR→C3H combination, mixed chimerism was maintained for as long as 100 days after tolerance induction in both the spleen and thymus, associated with intrathymic clonal deletion of Vβ6+ T cells. The decreases in leukocyte count, hemoglobin level, spleen weight, SC count, and body weight were significantly smaller in the SC+CP 66×3 group than in the SC+CP 200×1 group. Conclusions. Fractionated CP is effective in ameliorating the compromised state induced by a single dose of CP. To induce a long-lasting skin allograft survival associated with stable mixed chimerism and intrathymic clonal deletion in an H2-identical combination, 200 mg/kg of CP can be divided into three or fewer fractions.