Significant enhancement by anti-ICOS antibody of suboptimal tacrolimus immunosuppression in rat liver transplantation
Significant enhancement by anti-ICOS antibody of suboptimal tacrolimus immunosuppression in rat liver transplantation
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DOI：
10.1002/lt.20167
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发表时间：
2004-06-01
影响因子：
4.6
通讯作者：
Makuuchi, M
中科院分区：
文献类型：
--
作者：
Guo, L;Li, XK;Makuuchi, M
共刺激分子家族的一员，诱导型共刺激分子（ICOS），表达于活化的T细胞上，并在其初级活化和细胞因子产生中起关键作用。ICOS参与不同的免疫现象，如Thl介导的自身免疫性疾病和移植排斥。虽然阻断ICOS共刺激在理论上可以保护移植物免受排斥反应，但单剂量的抗ICOS抗体并没有导致大鼠肝移植物存活时间的延长。然而，在这篇文章中，我们报告说，抗大鼠ICOS抗体显着增强免疫抑制活性的次优剂量的他克莫司（FK 506）。在完全同种异体DA至LEW肝移植后，接受者接受单次注射他克莫司（lmg/kg，肌内），有或没有抗ICOS抗体（lmg/kg，静脉内）。在用抗体和次优他克莫司治疗的大鼠中，存活时间显著延长（中位存活时间44天对单独他克莫司治疗的28天，P <0.01）。移植物中细胞浸润的程度与受体存活时间的延长密切相关。因此，我们的研究结果表明，抗ICOS抗体免疫治疗结合次优他克莫司在预防肝移植排斥反应中具有协同作用，并且它可能诱导长期移植物接受与移植物内T淋巴细胞浸润的显着减少密切相关。
A member of the costimulatory molecule family, inducible costimulator (ICOS), is expressed on activated T cells and plays a critical role in their primary activation and cytokine production. ICOS is involved in different immune phenomena, such as Thl-mediated autoimmune disease and graft rejection. Although blockade of ICOS costimulation theoretically may protect grafts from rejection, a single dose of anti-ICOS antibody did not result in the prolongation of rat liver allograft survival. However, in this article, we report that anti-rat ICOS antibody markedly enhanced the immunosuppressive activity of a suboptimal dose of tacrolimus (FK506). After fully allogenic DA to LEW liver transplantation, recipients received a single injection of tacrolimus (1 mg/kg, intramuscularly) with or without anti-ICOS antibody (I mg/kg, intravenously). Recipient survival was significantly prolonged in rats treated with both the antibody and suboptimal tacrolimus (median survival time 44 days vs. 28 days with tacrolimus alone, P < .01). The extent of cell infiltration into the graft was closely associated with prolongation of recipient survival. Our findings thus demonstrate that anti-ICOS antibody immunotherapy combined with suboptimal tacrolimus has a synergistic effect in preventing hepatic allograft rejection and that it may induce longterm graft acceptance intimately associated with a marked reduction of intragraft T lymphocyte infiltration.