Downregulation of intragraft IFN-gamma expression correlates with increased IgG1 alloantibody response following intrathymic immunomodulation of sensitized rat recipients
Downregulation of intragraft IFN-gamma expression correlates with increased IgG1 alloantibody response following intrathymic immunomodulation of sensitized rat recipients
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DOI：
10.1097/00007890-199560120-00025
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发表时间：
1995-12-27
期刊：
影响因子：
6.2
通讯作者：
KupiecWeglinski, JW
中科院分区：
文献类型：
--
作者：
Binder, J;Graser, E;KupiecWeglinski, JW
单次胸腺内注射供体特异性脾细胞（2 × 10（7））可消除致敏LEW大鼠心脏移植物对LBNF（1）的加速排斥反应（24小时），移植物存活约11天。这种效应是供体特异性的、γ-辐射敏感的、胸腺依赖性的，并且不需要伴随治疗。我们最近表明，胸腺内同种异体抗原给药后，有一个更早和增加的同种异体反应性IgM的全身生产，随后过早的同种型转换为IgG与主要的IgG 1和IgG 2a同种抗体反应。这些IgG亚类也优先结合到功能良好的同种异体移植物的内皮上。在这项工作中，我们分析了早期细胞激活和相关的细胞因子的制作模式在mRNA和蛋白质水平的竞争性模板RT-PCR和免疫组化，分别。我们发现，在预致敏大鼠胸腺内注射供体脾细胞后，心脏移植物存活时间延长与移植物内IFN-γ mRNA和蛋白表达显著降低相关。此外，胸腺内同种异体刺激导致IL-2通路的缺陷，因为尽管IL-2 mRNA水平稳定，但移植部位的IL-2和IL-BR蛋白的表达受到抑制。通过免疫组织化学检测，MHC II类分子的减少和ICAM-1和TNF-α表达的缺乏也证明了细胞活化的抑制。在3 ~ 12小时的排斥移植物中检测到单核细胞和内皮细胞表达具有生物活性的IL-12（p70）。胸腺内同种异体刺激后功能良好的移植物缺乏IL-12（p70），这反过来可能导致IFN-γ mRNA和蛋白的下调。用r. IFN-γ治疗，而不是用r.IL-2治疗，重建了排斥反应，以及与加速移植物丢失相关的特征性IgG亚类模式。因此，同种异体抗原胸腺内免疫调节导致IFN-γ产生细胞的选择性抑制和IgG 1同种异体抗体的优先上调。这些数据支持的概念联锁的免疫调节作用的细胞因子和同种抗体网络在大鼠同种异体移植受体。
A single intrathymic injection of donor-specific spleen cells (2x10(7)) abrogates accelerated (24 hr) rejection of LBNF(1) cardiac allografts in presensitized LEW rats and prolongs graft survival to about 11 days. This effect is donor-specific, gamma-irradiation-sensitive, thymus-dependent, and requires no concomitant therapy. We have recently shown that following intrathymic alloantigen administration, there is an earlier and increased systemic production of alloreactive IgM, and subsequently a premature isotype switching to IgG with the predominant IgG1 and IgG2a alloantibody responses. There is also a preferential binding of these IgG: subclasses to the endothelium of well-functioning allografts. In this work, we analyzed the early cell activation and related cytokine elaboration patterns at the mRNA and protein levels by competitive template RT-PCR and immunohistochemistry, respectively. We found that prolonged cardiac allograft survival following intrathymic administration of donor spleen cells in presensitized rats was associated with markedly depressed intragraft IFN gamma mRNA and protein expression. Moreover, intrathymic allostimulation has led to a defect in the IL-2 pathway as the expression of IL-2 and IL-BR protein at the graft site was inhibited despite stable IL-2 mRNA levels. The inhibition of cell activation was also demonstrated by reduced MHC class II and the lack of ICAM-1, and TNF-alpha expression by immunohistochemistry. The expression of biologically active IL-12 (p70) by mononuclear and endothelial cells was detected in rejecting grafts between 3 and 12 hr. The well-functioning grafts after intrathymic allostimulation were devoid of IL-12 (p70), which in turn may have contributed to the downregulation of IFN-gamma mRNA and protein. Treatment with r.IFN-gamma, but not with r.IL-2, recreated the rejection response, and the characteristic IgG subclass pattern associated with accelerated graft loss. Hence, intrathymic immunomodulation with alloantigen results in selective inhibition of IFN-gamma-producing cells and a preferential upregulation of IgG1 alloantibodies. These data support the notion of the interlocked immunoregulatory roles of cytokine and alloantibody networks in rat allograft recipients.