Jacobs F, Dubois C, Carlier Y, Goldman M
Laboratoire Pluridisciplinaire de Recherche Expérimentale Biomédicale, Hôpital Erasme, Brussels, Belgium.
Clin Exp Immunol. 1996 Feb;103(2):233-8. doi: 10.1046/j.1365-2249.1996.d01-632.x.
The injection of the 145-2C11 anti-CD3 MoAb in mice induces a polyclonal T cell activation resulting in the release of several cytokines, including interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). As these cytokines are known to be involved in the host defence against Trypanosoma cruzi, we measured serum levels of IFN-gamma and TNF-alpha after injection of the 145-2C11 MoAb in the course of experimental murine Chagas' disease. Compared with control mice, T. cruzi-infected BALB/c mice were found to be primed to secrete very high levels of IFN-gamma and TNF-alpha from the second and the first week of infection, respectively, up to the chronic phase. In vivo cell depletion experiments indicated that CD8+ T cells were responsible for these dramatic hyperproductions of IFN-gamma and TNF-alpha. While all control mice survived anti-CD3 MoAb injection, a high lethality rate was observed in T. cruzi-infected mice within 24 h after anti-CD3 MoAb challenge. Pretreatment with neutralizing anti-IFN-gamma MoAb or depletion of CD8+ T cell population dramatically decreased the mortality induced by anti-CD3 MoAb in T. cruzi-infected mice. Finally, we showed that anti-CD3 MoAb injection in T. cruzi-infected mice was followed by a massive release of nitric oxide (NO) metabolites, which was partially reduced by IFN-gamma or TNF-alpha neutralization. The administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before anti-CD3 MoAb challenge did not prevent and even enhanced lethality in T. cruzi-infected mice, suggesting that NO overproduction and lethal shock are not causally related. We conclude that injection of anti-CD3 MoAb in the course of experimental Chagas' disease induces a CD8+ cell-dependent shock mediated by IFN-gamma and TNF-alpha.
给小鼠注射145 - 2C11抗CD3单克隆抗体可诱导多克隆T细胞活化，导致多种细胞因子释放，包括干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）。由于已知这些细胞因子参与宿主对抗克氏锥虫的防御，我们在实验性小鼠恰加斯病过程中注射145 - 2C11单克隆抗体后，测量了血清中IFN-γ和TNF-α的水平。与对照小鼠相比，发现克氏锥虫感染的BALB/c小鼠分别从感染的第二周和第一周开始，直至慢性期，都被激发分泌非常高水平的IFN-γ和TNF-α。体内细胞耗竭实验表明，CD8 + T细胞是这些IFN-γ和TNF-α大量过度产生的原因。虽然所有对照小鼠在注射抗CD3单克隆抗体后存活，但在克氏锥虫感染的小鼠中，抗CD3单克隆抗体攻击后24小时内观察到高致死率。用中和性抗IFN-γ单克隆抗体预处理或耗尽CD8 + T细胞群体可显著降低抗CD3单克隆抗体在克氏锥虫感染小鼠中诱导的死亡率。最后，我们表明在克氏锥虫感染的小鼠中注射抗CD3单克隆抗体后会伴随大量一氧化氮（NO）代谢产物的释放，IFN-γ或TNF-α中和可部分降低这种释放。在抗CD3单克隆抗体攻击前给予NO合酶抑制剂N-硝基-L-精氨酸甲酯（L-NAME）并不能预防甚至增强了克氏锥虫感染小鼠的致死率，这表明NO的过度产生与致死性休克没有因果关系。我们得出结论，在实验性恰加斯病过程中注射抗CD3单克隆抗体可诱导由IFN-γ和TNF-α介导的CD8 +细胞依赖性休克。
