Deckert-Schlüter M, Rang A, Weiner D, Huang S, Wiestler O D, Hof H, Schlüter D
Institut für Neuropathologie, Universitätskliniken Bonn, Germany.
Lab Invest. 1996 Dec;75(6):827-41.
Toxoplasma gondii may cause severe infections in immunocompromised patients including fetuses and those with AIDS. Among the factors mediating protection against T. gondii, IFN-gamma has gained special attention. To analyze the role of IFN-gamma in the early phase of toxoplasmosis, IFN-gamma receptor-deficient (IFN-gamma R0/0) mice were orally infected with low-virulent toxoplasms. IFN-gamma R0/0 mice died of the disease up to day 10 postinfection, whereas immunocompetent wild-type (WT) mice developed a chronic toxoplasmosis. Histopathology revealed that in IFN-gamma R0/0 mice, the parasite multiplied unrestrictedly in the small intestine, the intestinal lymphatic tissue, the liver, and the spleen. Ultimately, animals died of a necrotizing hepatitis. In WT mice, the same organs were effected, but multiplication of the parasite was effectively limited. Compared with WT mice, immunohistochemistry and flow cytometry demonstrated that in IFN-gamma R0/0 mice, macrophages were only marginally activated in response to the infection, as evidenced by a reduced expression of major histocompatability complex class II antigens. In addition, immunohistochemistry and RT-PCR showed a reduced production of the macrophage-derived cytokines tumor necrosis factor-alpha, inducible nitric oxide synthase, and IL-1 beta in the liver of IFN-gamma R0/0 mice. In contrast, activation of T cells, recruitment of immune cells to inflammatory foci, and anti-T. gondii IgM antibody production were unaffected by the mutation of the IFN-gamma R. Moreover, induction of IL-2, IL-4, and IL-10 mRNA transcripts in the liver was normal in IFN-gamma R0/0 mice. Adoptive transfer experiments revealed that the immune T cells of WT animals did not protect IFN-gamma R0/0 mice from lethal infection with highly virulent toxoplasms, whereas WT mice were significantly protected by the adoptive transfer. Based on these studies, we conclude that IFN-gamma is absolutely required for an efficient activation of macrophages. Macrophages are of critical importance in toxoplasmosis, and insufficient macrophage activation cannot be compensated by other immune mechanisms.
刚地弓形虫可在免疫功能低下的患者中引起严重感染，包括胎儿和艾滋病患者。在介导对刚地弓形虫防护的因素中，γ干扰素受到了特别关注。为分析γ干扰素在弓形虫病早期阶段的作用，将低毒力弓形虫经口感染γ干扰素受体缺陷（IFN-γR0/0）小鼠。IFN-γR0/0小鼠在感染后第10天死于该病，而具有免疫能力的野生型（WT）小鼠则发展为慢性弓形虫病。组织病理学显示，在IFN-γR0/0小鼠中，寄生虫在小肠、肠道淋巴组织、肝脏和脾脏中不受限制地繁殖。最终，动物死于坏死性肝炎。在WT小鼠中，相同的器官也受到影响，但寄生虫的繁殖受到有效限制。与WT小鼠相比，免疫组织化学和流式细胞术表明，在IFN-γR0/0小鼠中，巨噬细胞对感染的反应仅被轻微激活，这可通过主要组织相容性复合体II类抗原表达的降低得到证明。此外，免疫组织化学和逆转录-聚合酶链反应显示，IFN-γR0/0小鼠肝脏中巨噬细胞衍生的细胞因子肿瘤坏死因子-α、诱导型一氧化氮合酶和白细胞介素-1β的产生减少。相反，T细胞的激活、免疫细胞向炎症灶的募集以及抗刚地弓形虫IgM抗体的产生不受γ干扰素受体突变的影响。此外，IFN-γR0/0小鼠肝脏中白细胞介素-2、白细胞介素-4和白细胞介素-10 mRNA转录本的诱导是正常的。过继转移实验表明，WT动物的免疫T细胞不能保护IFN-γR0/0小鼠免受高毒力弓形虫的致命感染，而WT小鼠通过过继转移得到了显著保护。基于这些研究，我们得出结论，γ干扰素是有效激活巨噬细胞绝对必需的。巨噬细胞在弓形虫病中至关重要，巨噬细胞激活不足不能被其他免疫机制所补偿。
