Fowler D H, Kurasawa K, Husebekk A, Cohen P A, Gress R E
Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892.
J Immunol. 1994 Feb 1;152(3):1004-13.
A murine parent-into-F1 graft-vs-host reaction (GVHR) model that utilizes LPS to induce lethality was used to evaluate the in vivo regulatory role of donor cells of Th2 cytokine phenotype. Transfer of B6 spleen cells into B6C3F1 hosts was lethal when LPS endotoxin (15 micrograms) was administered on day 7 after cell transfer. Parental cells of Th2 cytokine phenotype were generated by treating B6 mice in vivo with a combination of IL-2 and IL-4 or with high dose IL-2. The CD4-enriched population from these cytokine-treated mice expressed and secreted increased levels of IL-4 and IL-10, with concomitantly decreased IL-2 and IFN-gamma. Cell mixing experiments (parental spleen cells+parental CD4-enriched. Th2-type cells) demonstrated that the Th2-type cells protected F1 hosts from LPS-induced lethality. These mice were analyzed to study possible mechanisms by which this protection was mediated. Compared with mice undergoing LPS-induced lethality during GVHR, Th2-protected mice had: 1) lower levels of donor CD8+ lymphoid engraftment, 2) in vivo suppression of IFN-gamma mRNA, 3) in vivo augmentation of IL-4 mRNA, and 4) a reduction in serum TNF-alpha. We thus conclude that donor cells of Th2 cytokine phenotype prevent LPS-induced, TNF-alpha-mediated lethality during GVHR, and that this protection is associated with regulation of both cellular- and cytokine-mediated events. As a result, we propose that cells of Th2 cytokine phenotype may represent a novel approach for establishing allogeneic lymphoid engraftment without lethal graft-vs-host disease.
利用脂多糖（LPS）诱导致死性的小鼠亲代到F1移植物抗宿主反应（GVHR）模型，用于评估Th2细胞因子表型供体细胞在体内的调节作用。当在细胞转移后第7天给予LPS内毒素（15微克）时，将B6脾细胞转移到B6C3F1宿主中是致死性的。通过用IL-2和IL-4组合或高剂量IL-2在体内处理B6小鼠，产生Th2细胞因子表型的亲代细胞。来自这些细胞因子处理小鼠的富含CD4的群体表达并分泌增加水平的IL-4和IL-10，同时IL-2和IFN-γ水平降低。细胞混合实验（亲代脾细胞+亲代富含CD4的Th2型细胞）表明，Th2型细胞可保护F1宿主免受LPS诱导的致死性。对这些小鼠进行分析以研究介导这种保护作用的可能机制。与在GVHR期间经历LPS诱导致死性的小鼠相比，Th2保护的小鼠具有：1）供体CD8 +淋巴细胞植入水平较低，2）体内IFN-γmRNA受到抑制，3）体内IL-4 mRNA增加，以及4）血清TNF-α降低。因此，我们得出结论，Th2细胞因子表型的供体细胞可预防GVHR期间LPS诱导的、TNF-α介导的致死性，并且这种保护作用与细胞介导和细胞因子介导事件的调节相关。因此，我们提出Th2细胞因子表型的细胞可能代表一种在不发生致死性移植物抗宿主病的情况下建立异基因淋巴细胞植入的新方法。
