Wilson M E, Young B M, Davidson B L, Mente K A, McGowan S E
Department of Internal Medicine, University of Iowa, Veterans Affairs Medical Center, Iowa City 52242, USA.
J Immunol. 1998 Dec 1;161(11):6148-55.
IFN-gamma is critical for the cure of leishmaniasis in humans and mice. BALB/c mice are genetically susceptible to infection with the visceralizing species of Leishmania, L. chagasi. We have evidence that a soluble factor(s) inhibits IFN-gamma production by cultured liver granuloma cells from BALB/c mice during L. chagasi infection. In contrast, liver granulomas from C3H.HeJ mice, which are genetically resistant to L. chagasi infection, produce abundant IFN-gamma. According to ELISAs and neutralization studies, there was not evidence that the Th2-type cytokines IL-10 or IL-4 contributed to IFN-gamma suppression. However, both Ab neutralization and immunohistochemistry showed that granuloma-derived TGF-beta was, at least in part, responsible for inhibiting IFN-gamma release by CD4+ cells in BALB/c liver granuloma cultures. Consistently, TGF-beta levels were high in liver granulomas from susceptible BALB/c mice but low in resistant C3H mice or in BALB/c mice that were immunized against L. chagasi disease. Administration of recombinant adenovirus expressing TGF-beta (AdV-TGFbeta) but not IL-10 (AdV-IL10) caused genetically resistant C3H mice to become significantly more susceptible to L. chagasi infection. In contrast, either AdV-TGFbeta or AdV-IL10 could abrogate the protective immune response achieved by immunization of BALB/c mice. We conclude that locally secreted TGF-beta inhibits Th1-associated cure of murine visceral leishmaniasis caused by L. chagasi, independently of Th2-type cytokines.
干扰素-γ对于人类和小鼠利什曼病的治愈至关重要。BALB/c小鼠在基因上易受内脏利什曼原虫（L. chagasi）感染。我们有证据表明，在L. chagasi感染期间，一种可溶性因子会抑制BALB/c小鼠培养的肝脏肉芽肿细胞产生干扰素-γ。相比之下，对L. chagasi感染具有基因抗性的C3H.HeJ小鼠的肝脏肉芽肿会产生大量干扰素-γ。根据酶联免疫吸附测定（ELISA）和中和研究，没有证据表明Th2型细胞因子白细胞介素-10（IL-10）或白细胞介素-4（IL-4）参与了干扰素-γ的抑制作用。然而，抗体中和及免疫组织化学均显示，肉芽肿来源的转化生长因子-β（TGF-β）至少部分负责抑制BALB/c肝脏肉芽肿培养物中CD4+细胞释放干扰素-γ。一致的是，易感的BALB/c小鼠肝脏肉芽肿中的TGF-β水平较高，而抗性的C3H小鼠或接种了针对L. chagasi病疫苗的BALB/c小鼠中的TGF-β水平较低。给予表达TGF-β的重组腺病毒（AdV-TGFβ）而非IL-10（AdV-IL10）会使基因抗性的C3H小鼠对L. chagasi感染的易感性显著增加。相反，AdV-TGFβ或AdV-IL10均可消除BALB/c小鼠免疫后获得的保护性免疫反应。我们得出结论，局部分泌的TGF-β独立于Th2型细胞因子，抑制了由L. chagasi引起的小鼠内脏利什曼病的Th1相关治愈。
