The specific monocarboxylate transporter (MCT1) inhibitor, AR-C117977, a novel immunosuppressant, prolongs allograft survival in the mouse
The specific monocarboxylate transporter (MCT1) inhibitor, AR-C117977, a novel immunosuppressant, prolongs allograft survival in the mouse
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DOI：
10.1097/01.tp.0000287543.91765.41
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发表时间：
2007-11-15
期刊：
影响因子：
6.2
通讯作者：
Wood, Kathryn
中科院分区：
文献类型：
--
作者：
Bueno, Valquiria;Binet, Isabelle;Wood, Kathryn
新的小分子化合物通过抑制单羧酸转运体(MCTI)受体的作用，已被发现在体外引起对同种异体抗原的T细胞反应的严重抑制。在这里，我们研究了这一系列化合物中的一种，AR-C117977，一种有效的MCT1抑制剂，在小鼠中预防血管化和非血管化同种异体移植物的急性和慢性排斥反应的能力。成年CBA皮下注射AR-C117977或环孢素A(CsA)30 mg/kg，连续15天。研究发现，在移植前3天或1天开始，CA(H2(K))小鼠的同种异体(C57BL/10 H2(B)；NZW H2 z；或BALB/c H2(D))心脏、主动脉或皮肤移植物的存活时间显著延长(B10、NZW和BALB)移植物的中位存活时间分别为15天、19天和18天、73天、66天和67天(B10、NZW和BALB分别为8天、8天和9天、9天、10天)。AR-C117977也能部分抑制移植物动脉硬化的发展，但不能抑制移植后同种抗体的产生。特异性MCTI抑制剂AR-C117977在体内具有强大的免疫抑制特性，有效地预防了小鼠移植急性排斥反应，但不能预防慢性排斥反应。
Novel small molecular weight compounds that act by inhibiting the monocarboxylate transporter (MCTI) receptor have been found to cause profound inhibition of T-cell responses to alloantigen in vitro. Here, we have investigated the ability of one compound in this series, AR-C117977, a potent MCT1 inhibitor, to prevent the acute and chronic rejection of vascularized and nonvascularized allografts in the mouse. Treatment with AR-C117977 or cyclosporin A (CsA) administered at a dose of 30 mg/kg subcutaneously for 15 days to adult CBA. Ca (H2(k)) mice, commencing either 3 days or 1 day before transplantation, was found to prolong the survival of an allogeneic (C57BL/10 H2(b); NZW H2z; or BALB/c H2(d)) heart, aorta, or skin allograft significantly compared with treatment with vehicle alone (median survival time [MST] AR-C117977 treated 15; 19 and 18 days [skin] and 73; 66 and 67 days ([heart] vs. vehicle treated 8,8 and 9 days [skin] and 9,8, 10 days [heart] for B10, NZW and BALB grafts, respectively). AR-C117977 also inhibited the development of transplant arteriosclerosis in aortic allografts partially, but was unable to inhibit alloantibody production after transplantation. The specific MCTI inhibitor AR-C117977 has potent immunosuppressive properties in vivo effectively preventing acute but not chronic allograft rejection in the mouse.