Division of Infectious Disease and Immunology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata, India.
Eur J Immunol. 2012 Aug;42(8):2087-99. doi: 10.1002/eji.201242428.
Resistance to murine visceral leishmaniasis (VL) correlates with the development of an IFN-γ predominant immune response. Beta1,4-galactose terminal glycans are potent inducers of IFN-γ. Here, we demonstrate the efficacy of a 29 kDa β1,4-galactose terminal glycoprotein (GP29) of Leishmania donovani (LD) in an in vitro macrophage model and an in vivo mouse model of VL. GP29 induced splenic macrophages to release NO and ROS in appreciable amounts that resulted in effective parasite clearance from macrophages. This was associated with the toll-like receptor (TLR)-4 mediated IL-12 induction and inhibition of TLR2-mediated IL-10 production. Two subcutaneous injections of GP29 at fortnightly intervals resulted in dominant IL-12-mediated IFN-γ production and 100% animals were protected against a subsequent challenge with virulent LD parasites. Vaccinated mice showed a reversal of T-cell anergy, significantly elevated expression of iNOS and a type-1 IgG subclass response. Moreover, vaccinated mice downregulated arginase1 and IL-10 expression but did not alter IL-4 expression. The IFN-γ/IL-10 ratio regulated the intensity of the protective immune response. Experiments with IFN-γ and IL-10 knockout mice reiterated the role IL-10 and IFN-γ play in disease progression or resolution in the murine model of VL.
对鼠内脏利什曼病 (VL) 的抗性与 IFN-γ 占主导的免疫反应的发展相关。β1,4-半乳糖末端糖基是 IFN-γ 的有效诱导物。在这里，我们在体外巨噬细胞模型和 VL 的体内小鼠模型中证明了 29 kDaβ1,4-半乳糖末端糖蛋白 (GP29) 的功效利什曼原虫 (LD)。GP29 诱导脾巨噬细胞释放大量的 NO 和 ROS，从而有效地从巨噬细胞中清除寄生虫。这与 TLR-4 介导的 IL-12 诱导和 TLR2 介导的 IL-10 产生抑制有关。每隔两周进行两次 GP29 皮下注射导致占主导地位的 TLR2 介导的 IL-12 诱导 IFN-γ 产生，并且 100%的动物受到保护，免受随后用强毒 LD 寄生虫的攻击。接种疫苗的小鼠表现出 T 细胞无反应性的逆转，显著增加了 iNOS 的表达和 1 型 IgG 亚类的反应。此外，接种疫苗的小鼠下调了精氨酸酶 1 和 IL-10 的表达，但不改变 IL-4 的表达。IFN-γ/IL-10 比值调节保护性免疫反应的强度。用 IFN-γ 和 IL-10 基因敲除小鼠进行的实验重申了 IL-10 和 IFN-γ 在 VL 小鼠模型中在疾病进展或消退中的作用。
