Alloantigen-reactive Th1 development in IL-12-deficient mice.
Alloantigen-reactive Th1 development in IL-12-deficient mice.
复制标题
DOI：
10.4049/jimmunol.160.3.1132
复制
发表时间：
1998-02
影响因子：
4.4
通讯作者：
J. Piccotti;Kewang Li;S. Chan;J. Ferrante;J. Magram;E. Eichwald;D. Bishop
中科院分区：
文献类型：
--
作者：
J. Piccotti;Kewang Li;S. Chan;J. Ferrante;J. Magram;E. Eichwald;D. Bishop
IL-12 p70是一种由二硫键结合的35-kDa（p35）和40-kDa（p40）亚基组成的70-至75-kDa异源二聚体，其主要通过其诱导NK和Th 1细胞产生IFN-γ的能力来增强Th 1发育。尽管IL-12的p40亚基的同源二聚体在某些系统中是有效的IL-12受体拮抗剂，但我们已经报道了p40同源二聚体可能加重同种异体反应性CD 8 + Th 1功能。为了测试内源性产生的p40在同种异体免疫中的作用，在IL-12 p35敲除（p35-/-）小鼠（其细胞能够分泌p40）或p40敲除（p40-/-）小鼠中评估Th 1发育。与IL-12野生型对照组相比，从p35-/-和p40-/-小鼠获得的脾细胞在体外用Con A或同种异体抗原刺激后产生的IFN-γ明显减少。有趣的是，在p35-/-和p40-/-心脏同种异体移植受者中检测到体内致敏的Th 1。然而，在体内Th 1的发展增强p35-/-受体与p40-/-动物相比，这表明内源性p40产生的p35-/-小鼠可能会刺激同种异体反应性Th 1。事实上，用抗IL-12 p40 mAb中和内源性p40使p35-/-同种异体移植物受体中的Th 1发育减少至p40-/-小鼠中所见。为了确定在缺乏IL-12 p70和p40的情况下发生的Th 1发育是否需要IFN-γ，用抗IFN-γ mAb治疗p40-/-同种异体移植物受体。中和IFN-γ并不抑制p40-/-受体体内Th 1的发育，并导致以血管血栓形成为特征的排斥反应的独特病理学。总的来说，这些数据表明：1）内源性p40可以在体内同种异体抗原特异性Th 1致敏中替代IL-12 p70，2）体内同种异体反应性Th 1的发展可能不依赖于IL-12和IFN-γ，这表明了替代的Th 1致敏途径。
IL-12p70, a 70- to 75-kDa heterodimer consisting of disulfide-bonded 35-kDa (p35) and 40-kDa (p40) subunits, enhances Th1 development primarily by its ability to induce IFN-gamma production by NK and Th1 cells. Although homodimers of the p40 subunit of IL-12 are potent IL-12 receptor antagonists in some systems, we have reported that p40 homodimer may accentuate alloreactive CD8+ Th1 function. To test the role of endogenously produced p40 in alloimmunity, Th1 development was assessed in either IL-12 p35 knockout (p35-/-) mice, the cells of which are capable of secreting p40, or p40 knockout (p40-/-) mice. Compared with IL-12 wild-type controls, splenocytes obtained from both p35-/- and p40-/- mice produced markedly less IFN-gamma after in vitro stimulation with Con A or alloantigens. Interestingly, in vivo-sensitized Th1 were detected in both p35-/- and p40-/- cardiac allograft recipients. However, in vivo Th1 development was enhanced in p35-/- recipients compared with p40-/- animals, suggesting that endogenous p40 produced in p35-/- mice may stimulate alloreactive Th1. Indeed, neutralizing endogenous p40 with anti-IL-12 p40 mAb reduced Th1 development in p35-/- allograft recipients to that seen in p40-/- mice. To determine whether Th1 development that occurred in the absence of IL-12p70 and p40 required IFN-gamma, p40-/- allograft recipients were treated with anti-IFN-gamma mAb. Neutralizing IFN-gamma did not inhibit in vivo Th1 development in p40-/- recipients and resulted in a unique pathology of rejection characterized by vascular thromboses. Collectively, these data suggest that 1) endogenous p40 may substitute for IL-12p70 in alloantigen-specific Th1 sensitization in vivo and 2) in vivo alloreactive Th1 development may occur independent of IL-12 and IFN-gamma, suggesting an alternate Th1-sensitizing pathway.