Gazzinelli R T, Wysocka M, Hayashi S, Denkers E Y, Hieny S, Caspar P, Trinchieri G, Sher A
Immunology and Cell Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1994 Sep 15;153(6):2533-43.
In vitro and in vivo studies were performed to assess the involvement of IL-12 in resistance to acute and chronic infection with an avirulent strain of Toxoplasma gondii. Our previous findings implicated macrophages as a major source of parasite-induced IL-12. This finding was confirmed by showing that peritoneal macrophages exposed to either live parasites or soluble tachyzoite Ags produce IL-12 protein. In mice, increased expression of IL-12 (p40) mRNA in both spleen and peritoneal cells was detected as early as 2 days postinfection. Treatment with neutralizing mAbs against IL-12 increased the susceptibility of C57BL/6, BALB/c, and severe combined immunodeficient (SCID) mice to acute infection, which resulted in 100% mortality within the first 15 days after parasite inoculation. In contrast, neutralization of endogenously produced IL-12 had no effect when given during chronic infection. In agreement with the survival data, treatment with anti-IL-12 resulted in decreased IFN-gamma and enhanced Th2 (IL-4 and IL-10) cytokine synthesis by splenocytes when given during acute, but not chronic, toxoplasmosis. Sorting experiments on spleen cells from acutely infected mice indicated that both CD4+ lymphocytes and NK1.1+/CD3- cells contribute to the early IFN-gamma response. In contrast, CD4+ cells were found to be the major source of the cytokine during chronic disease. Together, these results suggest that the stimulation of macrophage-derived IL-12 plays a major role in both the induction of resistance and Th1 cell subset selection in acute T. gondii infection, but may not be required to maintain established immunity.
进行了体外和体内研究，以评估白细胞介素-12（IL-12）在抵抗无毒力株刚地弓形虫急性和慢性感染中的作用。我们之前的研究结果表明巨噬细胞是寄生虫诱导的IL-12的主要来源。通过显示暴露于活寄生虫或可溶性速殖子抗原的腹腔巨噬细胞产生IL-12蛋白，这一发现得到了证实。在小鼠中，早在感染后2天就检测到脾脏和腹腔细胞中IL-12（p40）mRNA的表达增加。用抗IL-12中和单克隆抗体治疗增加了C57BL/6、BALB/c和严重联合免疫缺陷（SCID）小鼠对急性感染的易感性，这导致在接种寄生虫后的前15天内死亡率达100%。相反，在慢性感染期间给予内源性产生的IL-12的中和剂则没有效果。与生存数据一致，在急性弓形虫病而非慢性弓形虫病期间给予抗IL-12治疗，导致脾细胞中干扰素-γ（IFN-γ）减少，Th2（IL-4和IL-10）细胞因子合成增强。对急性感染小鼠的脾细胞进行分选实验表明，CD4+淋巴细胞和NK1.1+/CD3-细胞均对早期IFN-γ反应有贡献。相反，在慢性疾病期间发现CD4+细胞是细胞因子的主要来源。总之，这些结果表明，巨噬细胞衍生的IL-12的刺激在急性刚地弓形虫感染的抗性诱导和Th1细胞亚群选择中均起主要作用，但维持已建立的免疫力可能不需要它。
