Baan Carla C, Balk Aggie H M M, Dijke I Esmé, Korevaar Sander S, Peeters Annemiek M A, de Kuiper Ronella P, Klepper Mariska, Zondervan Pieter E, Maat Lex A P W M, Weimar Willem
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
Transplantation. 2007 Jun 15;83(11):1485-92. doi: 10.1097/01.tp.0000264998.23349.54.
Interleukin (IL)-21 is the most recently described cytokine that signals via the common cytokine receptor (gammac), is produced by activated CD4+ T-cells, and regulates expansion and effector function of CD8+ T-cells.
To explore the actions of IL-21 with other gammac-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R alpha-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions. Additionally, IL-21 and IL-21R alpha-chain expression was studied in biopsies of heart transplant patients.
Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R alpha-chain. Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R alpha-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated. IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21. Blockade of the IL-21 route by anti-IL-21R alpha-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells. Also, in vivo alloreactivity was associated with IL-21/IL-21R alpha-chain expression. After heart transplantation, the highest intragraft IL-21, IL-21R alpha-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.001, P=0.01, P=0.03).
IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.
白细胞介素（IL）-21是最近描述的一种细胞因子，通过共同细胞因子受体（γc）发出信号，由活化的CD4 + T细胞产生，并调节CD8 + T细胞的扩增和效应功能。
为了探究IL-21与其他γc依赖性细胞因子在同种异体反应性中的作用，在混合淋巴细胞反应刺激后，测量了IL-21、IL-21Rα链的mRNA表达以及IL-2的增殖和细胞毒性。此外，还研究了心脏移植患者活检组织中IL-21和IL-21Rα链的表达。
对同种异体刺激的T细胞mRNA表达水平的分析显示，IL-21和IL-21Rα链的诱导增加了10倍。有趣的是，IL-21的诱导高度依赖于IL-2（如在存在抗IL-2、抗IL-2Rα链以及免疫抑制药物环孢素A、他克莫司和雷帕霉素的情况下），IL-21的转录几乎完全受到抑制，而在存在外源性IL-2的情况下，IL-21的mRNA表达甚至进一步上调。IL-21作为IL-2的共刺激因子，增强增殖和细胞毒性反应，而阻断IL-2途径则消除了IL-21的这些功能。抗IL-21Rα链单克隆抗体阻断IL-21途径可抑制同种异体活化T细胞的增殖。此外，体内同种异体反应性与IL-21/IL-21Rα链表达相关。心脏移植后，在急性排斥反应期间测量到移植物内IL-21、IL-21Rα链和IL-2 mRNA的最高表达水平（P<0.001，P = 0.01，P = 0.03）。
IL-21是IL-2依赖性免疫过程的关键细胞因子。阻断IL-21途径可能为移植后患者同种异体反应的治疗提供新的视角。
