Takahashi M, Shimizu H, Murakami T, Enosawa S, Suzuki C, Takeno Y, Hakamata Y, Kudou S, Izawa S, Yasue T, Kobayashi E
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Transplant Proc. 2005 Jan-Feb;37(1):143-5. doi: 10.1016/j.transproceed.2004.12.107.
To find more effective and less toxic immunosuppressive strategies in long-term treatment for organ transplantation patients, we examined the effects on rat heart allograft survival of a novel sphigosine-1-phosphate receptor agonist, KRP-203, combined with a subtherapeutic dose of cyclosporine (CsA). Rat heart transplantation was performed across a major histocompatibility complex-incompatible (DA to LEW) rat combination. KRP-203 alone showed little or no effect on heart allograft survival. In contrast, KRP-203 combined with a subtherapeutic dose of CsA led to prolonged allograft survival. Histologic analyses showed that the combination completely suppressed acute rejection, as characterized by allograft vasculopathy, mononuclear cell infiltration, and myocardial necrosis in the heart allografts. RT-PCR analysis showed that the allografts treated with CsA or KRP-203 alone showed no suppression of IL-10, IFN-gamma, and TNF-alpha mRNA expression, but when combined with a subtherapeutic dose of CsA it completely suppressed their mRNA expressions. Furthermore, the combination treatment reduced donor-specific antibody production. KRP-203 combined with a subtherapeutic dose of CsA synergistically prolonged rat heart allograft survival. The combination of CsA with KRP-203 may provide an option to prevent allograft rejection and reduce adverse effects.
为了在器官移植患者的长期治疗中找到更有效且毒性更低的免疫抑制策略，我们研究了新型鞘氨醇-1-磷酸受体激动剂KRP-203与亚治疗剂量环孢素（CsA）联合使用对大鼠心脏同种异体移植存活的影响。大鼠心脏移植是在主要组织相容性复合体不相容（DA到LEW）的大鼠组合中进行的。单独使用KRP-203对心脏同种异体移植存活几乎没有影响。相比之下，KRP-203与亚治疗剂量的CsA联合使用可延长同种异体移植的存活时间。组织学分析表明，该组合完全抑制了急性排斥反应，其特征为同种异体移植血管病变、单核细胞浸润和心脏同种异体移植中的心肌坏死。逆转录聚合酶链反应（RT-PCR）分析表明，单独用CsA或KRP-203处理的同种异体移植未显示白细胞介素-10（IL-10）、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）信使核糖核酸（mRNA）表达受到抑制，但与亚治疗剂量的CsA联合使用时，它完全抑制了它们的mRNA表达。此外，联合治疗减少了供体特异性抗体的产生。KRP-203与亚治疗剂量的CsA联合使用可协同延长大鼠心脏同种异体移植的存活时间。CsA与KRP-203的联合使用可能为预防同种异体移植排斥反应和减少不良反应提供一种选择。
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