Zhou Dejun, O'Brien Catherine, Shum Jeffrey, Garcia Bertha, Min Weiping, Jevnikar Anthony M, Dutartre Patrick, Zhong Robert
Department of Surgery, The University of Western Ontario, London, Ontario, Canada.
Transplantation. 2003 Aug 27;76(4):644-50. doi: 10.1097/01.TP.0000071202.91772.90.
LF 15-0195 (LF) is a new analogue of 15-deoxyspergualin (DSG) that is less toxic and more potent than DSG. The present study was undertaken to determine (1). the dose response of LF monotherapy, (2). its ability to induce tolerance, and (3) its interaction with cyclosporine (CsA), FK 506 (FK), and rapamycin (RAPA).
Varying doses of LF were administered to determine dose-dependent effects on graft survival in a C57BL/6 to BALB/c heterotopic heart allograft mouse model. Transplanting-donor and third-party skin grafts into long-term survivors were used to assess the tolerance status. CsA, FK, and RAPA were combined with LF to determine their interactive effects on graft survival.
The efficacy and toxicity of LF was dose dependent. High-dose LF monotherapy (>2 mg/kg) induced donor-specific operational tolerance, but it was associated with high mortality. Simultaneous administration of high-dose calcineurin inhibitors (CsA FK) prevented tolerance induced by LF. In contrast, a short course of LF combined with a subtherapeutic dose of CsA FK achieved indefinite survival of C57/BL6 cardiac allografts. RAPA and LF had a synergistic effect in induction of tolerance.
The efficacy and toxicity of LF were dose dependent. A short course of LF significantly reduced the requirement of CsA or FK to prevent rejection. RAPA and LF had synergy in induction of tolerance. These data indicate that LF may be a promising agent that warrants further studies in nonhuman primate models of transplantation.
LF 15-0195（LF）是15-脱氧精胍菌素（DSG）的一种新类似物，其毒性低于DSG且效力更强。本研究旨在确定：（1）LF单一疗法的剂量反应；（2）其诱导耐受的能力；（3）其与环孢素（CsA）、FK 506（FK）和雷帕霉素（RAPA）的相互作用。
在C57BL/6到BALB/c异位心脏同种异体移植小鼠模型中，给予不同剂量的LF以确定其对移植物存活的剂量依赖性影响。将供体和第三方皮肤移植物移植到长期存活者体内以评估耐受状态。将CsA、FK和RAPA与LF联合使用以确定它们对移植物存活的相互作用。
LF的疗效和毒性具有剂量依赖性。高剂量LF单一疗法（>2mg/kg）可诱导供体特异性操作性耐受，但与高死亡率相关。同时给予高剂量钙调神经磷酸酶抑制剂（CsA、FK）可阻止LF诱导的耐受。相比之下，短疗程的LF与亚治疗剂量的CsA、FK联合可使C57/BL6心脏同种异体移植物获得长期存活。RAPA和LF在诱导耐受方面具有协同作用。
LF的疗效和毒性具有剂量依赖性。短疗程的LF可显著降低预防排斥反应所需的CsA或FK剂量。RAPA和LF在诱导耐受方面具有协同作用。这些数据表明，LF可能是一种有前景的药物，值得在非人类灵长类动物移植模型中进一步研究。
