Torrico F, Heremans H, Rivera M T, Van Marck E, Billiau A, Carlier Y
Laboratory of Parasitology, Faculty of Medicine, University of Brussels, Belgium.
J Immunol. 1991 May 15;146(10):3626-32.
In order to study the role of endogenous IFN-gamma in Trypanosoma cruzi infection in mice, a potent murine IFN-gamma-specific mAb was injected i.p. on days -1, 7, and 14, relative to infection. Irrespective of the parasite inocula (100 or 25,000), groups of antibody-treated mice had significantly greater cumulative mortality rates than did appropriate controls. In antibody-treated mice, mean survival times were also significantly shorter, and maximum mean parasitemia levels were significantly higher, than in controls. Moreover, the number of amastigote nests in tissues was higher than in control mice and attained a maximum at the same time as parasitemia. As evident from kinetic studies of neutralizing activity, injected mAb were rapidly consumed in infected, but not in noninfected, mice, which is suggestive of massive IFN-gamma production during the early parasitemic phase of the disease. Nevertheless, IFN-gamma remained undetectable in the sera of infected but untreated mice. Unexpectedly, however, a peak of IFN-like antiviral activity, characterizable as a mixture of IFN-gamma and IFN-beta, appeared in mAb-treated mice that survived to infection at a time when neutralizing activity of injected mAb had drastically decreased in the circulation. We hypothesize that this high level of artificially induced endogenous IFN-gamma, not neutralized by the amounts of injected mAb, was due to the more intense parasite multiplication occurring in mAb-treated mice, which in turn may have induced an increased amount of various cytokines. TNF-alpha was not found in the serum of our mice. The humoral immune response entered its exponential phase at a time point later than that when protection by endogenous IFN-gamma was evident. Treatment with IFN-gamma-specific antibody, as applied in our study, failed to affect the level of different Ig isotypes or of T. cruzi-specific antibodies. Our study clearly indicates that IFN-gamma is produced early in acute T. cruzi infection and exerts a protective effect that is probably independent from the humoral immune response.
为研究内源性干扰素-γ在小鼠克氏锥虫感染中的作用，在感染前第-1天、第7天和第14天腹腔注射一种强效的鼠源干扰素-γ特异性单克隆抗体。无论寄生虫接种量如何（100或25000），抗体处理组小鼠的累积死亡率均显著高于相应对照组。在抗体处理的小鼠中，平均存活时间也显著缩短，最大平均寄生虫血症水平显著高于对照组。此外，组织中无鞭毛体巢的数量高于对照小鼠，并与寄生虫血症同时达到最大值。从中和活性的动力学研究可以明显看出，注射的单克隆抗体在感染小鼠中迅速消耗，但在未感染小鼠中则不然，这表明在疾病的早期寄生虫血症阶段有大量干扰素-γ产生。然而，在感染但未治疗的小鼠血清中仍未检测到干扰素-γ。然而，出乎意料的是，在存活至感染的单克隆抗体处理小鼠中，出现了一个类似干扰素的抗病毒活性峰值，其特征为干扰素-γ和干扰素-β的混合物，此时注射的单克隆抗体在循环中的中和活性已大幅下降。我们推测，这种高水平的人工诱导内源性干扰素-γ未被注射的单克隆抗体中和，是由于在单克隆抗体处理的小鼠中寄生虫繁殖更为强烈，这反过来可能诱导了各种细胞因子产生量的增加。在我们小鼠的血清中未发现肿瘤坏死因子-α。体液免疫反应进入指数期的时间点晚于内源性干扰素-γ发挥保护作用的明显时间点。如我们研究中所应用的，用干扰素-γ特异性抗体处理未能影响不同免疫球蛋白亚型或克氏锥虫特异性抗体的水平。我们的研究清楚地表明，干扰素-γ在急性克氏锥虫感染早期产生，并发挥可能独立于体液免疫反应的保护作用。
