IL-12 antagonism induces T helper 2 responses, yet exacerbates cardiac allograft rejection. Evidence against a dominant protective role for T helper 2 cytokines in alloimmunity.
IL-12 antagonism induces T helper 2 responses, yet exacerbates cardiac allograft rejection. Evidence against a dominant protective role for T helper 2 cytokines in alloimmunity.
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DOI：
10.4049/jimmunol.157.5.1951
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发表时间：
1996-09
影响因子：
4.4
通讯作者：
J. Piccotti;S. Chan;R. Goodman;J. Magram;E. Eichwald;D. Bishop
中科院分区：
文献类型：
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作者：
J. Piccotti;S. Chan;R. Goodman;J. Magram;E. Eichwald;D. Bishop
IL-12促进Th 1发育并通过诱导IFN-γ产生来抑制Th 2的产生。在几种实验模型中，Th 2在不存在IL-12的情况下优先诱导。有人提出，通过IL-12拮抗作用优先诱导Th 2将抑制Th 1驱动的排斥反应，从而促进同种异体移植物接受。为了测试这种可能性，用抗IL-12 Ab或用IL-12受体拮抗剂p40同型二聚体处理小鼠心脏同种异体移植物受体。未修饰的排斥反应的特征在于Th 1主导的反应，其中Th 2细胞因子在同种异体移植物内不存在或仅弱表达。尽管两种形式的IL-12拮抗作用都诱导了同种异体移植物内的Th 2细胞因子表达，但相对于对照动物，这些治疗令人惊讶地加剧了移植排斥反应。有趣的是，IL-12拮抗作用不抑制IFN-γ基因表达或IFN-γ产生细胞的体内致敏作用。当使用IL-12 p40敲除小鼠作为同种异体移植物供体和受体时，进行了类似的观察，验证了IL-12对于Th 1发育不是必需的。此外，IL-12拮抗作用与移植物内p40的强表达和p35的弱表达相关。在对照同种异体移植物中均未检测到p35和p40 mRNA。这些数据表明，虽然IL-12拮抗作用确实诱导Th 2细胞因子在心脏同种异体移植物中的表达，但Th 2细胞因子在排斥反应过程中并不起主要的保护作用。此外，IL-12拮抗作用的Th 2诱导活性与IFN-γ产生减少无关，但可能反映了IL-12本身调节的改变。
IL-12 promotes Th1 development and inhibits the generation of Th2 by inducing IFN-gamma production. In several experimental models, Th2 are preferentially induced in the absence of IL-12. It was proposed that the preferential induction of Th2 by IL-12 antagonism would inhibit Th1-driven rejection responses, thereby promoting allograft acceptance. To test this possibility, mouse cardiac allograft recipients were treated with either anti-IL-12 Abs, or with the IL-12 receptor antagonist p40 homodimer. Unmodified rejection is characterized by a Th1-dominated response, with Th2 cytokines being absent or only weakly expressed within the allograft. Though both forms of IL-12 antagonism induced Th2 cytokine expression within the allograft, these treatments surprisingly exacerbated graft rejection relative to control animals. Interestingly, IL-12 antagonism did not inhibit IFN-gamma gene expression or in vivo sensitization of IFN-gamma-producing cells. Similar observations were made when IL-12 p40 knockout mice were used as allograft donors and recipients, verifying that IL-12 was not required for Th1 development. Further, IL-12 antagonism was associated with strong expression of p40 and weak expression of p35 within the graft. Neither p35 nor p40 mRNAs were detectable in control allografts. These data indicate that while IL-12 antagonism does induce Th2 cytokine expression within cardiac allografts, Th2 cytokines do not play a dominant protective role in the rejection process. Further, the Th2-inducing activity of IL-12 antagonism is not related to decreased IFN-gamma production, but may reflect altered regulation of IL-12 itself.