IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.
IL-2 and IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors in allograft rejection.
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DOI：
10.4049/jimmunol.161.2.890
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发表时间：
1998-07
影响因子：
4.4
通讯作者：
Xian Chang Li;Prabir Roy-Chaudhury;Wayne W. Hancock;R. Manfro;Martin S. Zand;Yongsheng Li;X. Zheng;Peter W. Nickerson;Jürg Steiger;T. Malek;Terry B. Strom
中科院分区：
文献类型：
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作者：
Xian Chang Li;Prabir Roy-Chaudhury;Wayne W. Hancock;R. Manfro;Martin S. Zand;Yongsheng Li;X. Zheng;Peter W. Nickerson;Jürg Steiger;T. Malek;Terry B. Strom
T细胞生长因子(TCGF)通过促进同种异体反应性T细胞的活化和增殖，在同种异体移植排斥反应中发挥重要作用。为了确定IL-2和IL-4是否在同种异体移植排斥反应中起着典型的重要作用，并寻找可能的替代TCGF，我们培育了IL-2(-/-)和IL-4(-/-)双基因敲除(DKO)小鼠，并以DKO小鼠作为同种异体移植受体来研究胰岛移植排斥反应。虽然DKO小鼠的单核白细胞在体外对抗CD3刺激不能产生增殖反应，但DKO小鼠对粗制同种异体胰岛移植物的排斥反应(平均存活时间为17+/-7，n=8)明显高于野生型对照组(平均存活时间为13+/-4，n=7)。用抗CD3抗体或雷帕霉素处理DKO小鼠，可显著延长胰岛移植物的存活时间。对移植体内细胞因子基因转录本的分析显示，IL-7和IL-15表达强劲。相反，无论是野生型还是DKO小鼠，移植体内的IL-9基因转录本都没有检测到。提供外源性IL-2、IL-4、IL-7或IL-15，而不提供IL-9，支持体外抗CD3激活的DKO脾白细胞的增殖。阻断IL-2受体的共同伽马C，IL-2受体是IL-2、IL-4、IL-7、IL-9和IL-15受体共同的基本信号成分，可以延长DKO小鼠同种异体胰岛移植物的存活时间。因此，在缺乏IL-2和IL-4的情况下，雷帕霉素敏感信号或伽马C链结合介导的信号使T细胞依赖的同种异体移植排斥反应发生。非T细胞来源的TCGF，尤其是IL-7和IL-15，可能在支持同种异体移植排斥反应中发挥积极作用。
T cell growth factors (TCGFs) play a critical role in allograft rejection by promoting the activation and proliferation of alloreactive T cells. To determine whether IL-2 and IL-4 are of quintessential importance in allograft rejection and to identify possible alternative TCGFs, we have bred IL-2(-/-) and IL-4(-/-) double knockout (DKO) mice and studied islet allograft rejection using the DKO mice as allograft recipients. Although mononuclear leukocytes from DKO mice did not mount a proliferative response in vitro in response to anti-CD3 stimulation, crude islet allografts were vigorously rejected by DKO mice (mean survival time 17 +/- 7, n = 8) as compared with wild-type controls (mean survival time 13 +/- 4, n = 7). Treatment of DKO mice with anti-CD3 or rapamycin markedly prolonged the islet allograft survival. An analysis of intragraft cytokine gene transcripts showed robust expression of IL-7 and IL-15. In contrast, intragraft IL-9 gene transcripts were not detected in either wild-type or DKO mice. Provision of exogenous IL-2, IL-4, IL-7, or IL-15, but not IL-9, supports the proliferation of anti-CD3 activated DKO splenic leukocytes in vitro. Blocking the common gamma c of IL-2 receptor, a shared essential signaling component by receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, prolonged the survival of islet allografts in DKO mice. Hence, a T cell dependent allograft rejection enabled by rapamycin-sensitive signals or signals mediated by binding of the gamma c chain occurs in the absence of both IL-2 and IL-4. Non-T cell-derived TCGFs, especially IL-7 and IL-15, may play an active role in supporting allograft rejection.