De Fazio S R, Plowey J M, Hartner W C, Gozzo J J
Department of Pharmaceutical Science, Bouvé College of Pharmacy and Health Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
Transpl Immunol. 1996 Jun;4(2):105-12. doi: 10.1016/s0966-3274(96)80003-7.
Temporary donor-specific unresponsiveness induced by treatment of skin allografted mice with antilymphocyte serum (ALS) and donor bone marrow cells (BMC) can be converted to long-term graft survival and tolerance by adding adjunctive immunosuppressive agents, including rapamycin (Rapa). Rapa was given in a suboptimal dosing schedule to probe several aspects of its use in the promotion of tolerization. Single doses were given at 2 weeks post-transplantation to recipients prepared with ALS and donor BMC. Graft survival was markedly prolonged in a dose-dependent fashion by day +14, Rapa doses ranging from 0.75 to 6.0 mg/kg. Indefinite (> 300 day) graft survival was observed in 26% of recipients given the highest Rapa dose. Short-term treatment with cyclosporin A (CsA) or deoxyspergualin (DSG) was ineffective when injected at this time. Rapa augmented the tolerizing effect of grafting with skin from newborn mice but had no significant additive or synergistic effects with the short course of CsA or with DSG given on days +1 to +3, even though the latter prolonged graft survival when added to the ALS/BMC protocol. Single doses of Rapa on day +1 also prolonged graft survival, but without any of the grafts surviving indefinitely. Later dosing on day +28 resulted in > 70% of grafts surviving > 300 days. Challenge grafting of these mice after day +300 resulted in delayed rejection of donor strain, but not third-party skin grafts. Rapa was very effective when given as widely spaced doses on days +14 and +49. Also, grafts showing the earliest signs of rejection could be rescued with a single Rapa dose in recipients treated with ALS and BMC but not ALS alone. Transfer of prolonged graft survival with spleen cells from ALS plus BMC treated recipients was not adversely affected by Rapa given to the suppressor-like spleen cell donors approximately 1 week before cell harvest. We conclude that the use of Rapa as an adjunctive agent in allograft recipients treated with ALS plus donor BMC is very flexible in terms of timing of administration, and that the drug can be effectively given as widely spaced doses or as a rescue agent after ALS/BMC treatment. Additionally, an active immunoregulatory mechanism induced by ALS/BMC treatment appears to be spared by Rapa.
用抗淋巴细胞血清（ALS）和供体骨髓细胞（BMC）处理皮肤移植小鼠所诱导的暂时性供体特异性无反应性，可通过添加包括雷帕霉素（Rapa）在内的辅助免疫抑制剂，转化为长期移植物存活和耐受。以次优给药方案给予Rapa，以探究其在促进耐受方面的几个应用方面。在移植后2周给用ALS和供体BMC预处理的受体单次给药。到第14天时，Rapa剂量在0.75至6.0mg/kg范围内，移植物存活以剂量依赖性方式显著延长。给予最高Rapa剂量的受体中，26%观察到移植物无限期（>300天）存活。此时注射环孢素A（CsA）或脱氧精胍菌素（DSG）进行短期治疗无效。Rapa增强了用新生小鼠皮肤移植的耐受效果，但与在第1至3天给予的短期CsA或DSG无显著相加或协同作用，尽管后者添加到ALS/BMC方案中时可延长移植物存活。在第1天单次给予Rapa也可延长移植物存活，但没有移植物无限期存活。在第28天给药则导致>70%的移植物存活>300天。在第300天后对这些小鼠进行挑战性移植，导致供体品系的排斥反应延迟，但对第三方皮肤移植无此作用。在第14天和第49天以间隔较大的剂量给予Rapa非常有效。此外，在用ALS和BMC而非仅用ALS处理的受体中，显示出最早排斥迹象的移植物可用单次Rapa剂量挽救。在用ALS加BMC处理的受体中，在收获细胞前约1周给予Rapa给类似抑制性脾细胞供体，延长的移植物存活的脾细胞转移未受到不利影响。我们得出结论，在接受ALS加供体BMC治疗的同种异体移植受体中，将Rapa用作辅助剂在给药时间方面非常灵活，并且该药物可以以间隔较大的剂量有效给药或在ALS/BMC治疗后用作挽救剂。此外，ALS/BMC治疗诱导的一种活跃的免疫调节机制似乎不受Rapa影响。
