Saha B, Das G, Vohra H, Ganguly N K, Mishra G C
Immunology Lab, Institute of Microbial Technology, Chandigarh, India.
Eur J Immunol. 1995 Sep;25(9):2492-8. doi: 10.1002/eji.1830250913.
The most important immunopathological consequence of infection with Leishmania seen in murine and human hosts is the suppression of T cell-mediated immune responses to both mitogens and leishmanial antigens. It has been suggested that this suppression is mediated by macrophages, either by defective antigen processing and presentation or by the elaboration of suppressive mediators like prostaglandins. Optimum activation of T helper cells requires not only T cell receptor occupancy by the antigen-Ia complex, but also costimulatory signals provided by the antigen-presenting cells. We investigated the status of several costimulatory molecules on infected macrophages from both genetically susceptible BALB/c and resistant C57BL/6 mice. Our results demonstrate that upon parasitization, the macrophages become unable to deliver costimulatory signals to T helper cells, and that this effects is mediated by prostaglandins, as the inhibition of its synthesis by indomethacin recovered the defect. Upon infection with L. donovani, B7-1 expression was decreased, while ICAM-1 was marginally increased in BALB/c macrophages and there was no significant change in the expression of B7-1 and ICAM-1 in Leishmania-infected C57BL/6 macrophages. Expression of VCAM-1 did not change during infection. This selective alteration in the expression of costimulatory molecules on L. donovani-infected BALB/c macrophages was caused by the living parasite, as shown by the fact that killing of the parasites by stibogluconate led to no alteration in the levels of costimulatory molecules. We found that the change in B7-1 expression on the surface of infected macrophages resulted in the inhibition of delayed-type hypersensitivity-mediating functions of T helper cells from BALB/c mice. The results described in this study not only throw light on the possible mechanism of leishmanial pathogenesis, but also open up the possibility of immunotherapy of leishmaniasis by selective manipulation of costimulatory molecules.
在鼠类和人类宿主中，利什曼原虫感染最重要的免疫病理后果是T细胞介导的对丝裂原和利什曼原虫抗原的免疫反应受到抑制。有人提出，这种抑制是由巨噬细胞介导的，要么是通过缺陷的抗原加工和呈递，要么是通过诸如前列腺素等抑制性介质的分泌。T辅助细胞的最佳激活不仅需要抗原-Ia复合物占据T细胞受体，还需要抗原呈递细胞提供的共刺激信号。我们研究了来自基因易感的BALB/c小鼠和抗性C57BL/6小鼠的感染巨噬细胞上几种共刺激分子的状态。我们的结果表明，在被寄生后，巨噬细胞无法向T辅助细胞传递共刺激信号，并且这种效应是由前列腺素介导的，因为吲哚美辛对其合成的抑制恢复了缺陷。感染杜氏利什曼原虫后，BALB/c巨噬细胞中B7-1表达降低，而ICAM-1略有增加，在利什曼原虫感染的C57BL/6巨噬细胞中B7-1和ICAM-1的表达没有显著变化。感染期间VCAM-1的表达没有改变。杜氏利什曼原虫感染的BALB/c巨噬细胞上共刺激分子表达的这种选择性改变是由活寄生虫引起的，这一事实表明，葡萄糖酸锑钠杀死寄生虫不会导致共刺激分子水平的改变。我们发现，感染巨噬细胞表面B7-1表达的变化导致BALB/c小鼠T辅助细胞介导的迟发型超敏反应功能受到抑制。本研究中描述的结果不仅揭示了利什曼原虫发病机制的可能机制，还为通过选择性操纵共刺激分子进行利什曼病免疫治疗开辟了可能性。
