Stevenson M M, Tam M F, Belosevic M, van der Meide P H, Podoba J E
Centre for the Study of Host Resistance, Montreal General Hospital Research Institute, Quebec, Canada.
Infect Immun. 1990 Oct;58(10):3225-32. doi: 10.1128/iai.58.10.3225-3232.1990.
The role of gamma interferon (IFN-gamma), a pluripotent lymphokine capable of activating macrophages, in acquired immunity to blood-stage malaria was investigated. C57BL-derived, lipopolysaccharide-resistant C57BL/10ScN mice, which were found to be resistant to intraperitoneal (i.p.) infection with 10(6) Plasmodium chabaudi AS parasitized erythrocytes, were treated with monoclonal anti-IFN-gamma antibody (MAb). Two MAbs were used: R4-6A2, a rat anti-mouse, neutralizing immunoglobulin G1, which was prepared against natural murine IFN-gamma, and DB-1, a murine anti-rat immunoglobulin G1 prepared against recombinant rat IFN-gamma, which can neutralize the murine molecule as well as the rat molecule. C57BL/10ScNH mice were injected i.p. with 200 micrograms of R4-6A2 1 day before infection and every 3 days through day 21. Control mice were treated with normal rat serum. In separate experiments, DB-1 (1.0 mg per week for 4 weeks) was administered i.p. to C57BL/10ScNH mice beginning on the day of infection; control mice were untreated. Control and MAb-treated mice were infected i.p. with 10(6) P. chabaudi AS parasitized erythrocytes, and the course and outcome of infection were determined. Control mice exhibited a course of infection that was characterized by a peak parasitemia between 30 and 40% parasitized erythrocytes and elimination of the parasite by 4 weeks. MAb-treated mice exhibited a significantly greater parasitemia 1 to 2 days before the peak parasitemia as well as a significantly greater peak parasitemia but also completely cleared the infection by 4 weeks. Thus, these results suggest that treatment with anti-IFN-gamma MAb impairs but does not completely abrogate host resistance to P. chabaudi AS. We also examined the kinetics of IFN-gamma production by spleen cells cultured in vitro with malaria antigen or concanavalin A. Spleen cells were recovered from individual C57BL/6 mice at various times after i.p. infection with 10(6) P. chabaudi AS parasitized erythrocytes. The amount of IFN-gamma produced was quantitated by enzyme-linked immunosorbent assay. In each case, the peak of IFN-gamma production occurred just before the peak parasitemia, followed by a decrease to little or no IFN-gamma production through 42 days postinfection. There was thus a parallel between the kinetics of production of IFN-gamma in vitro by spleen cells from infected animals and the requirement in vivo for the endogenous molecule just before and at the time of peak parasitemia. In conclusion, these results suggest that IFN-gamma-dependent and -independent mechanisms contribute to host resistance to P. chabaudi AS.
研究了γ干扰素（IFN-γ）在获得性血液期疟疾免疫中的作用，γ干扰素是一种能够激活巨噬细胞的多能淋巴因子。发现C57BL衍生的抗脂多糖C57BL/10ScN小鼠对腹腔内（i.p.）感染10⁶ 感染查巴迪疟原虫AS的寄生红细胞具有抗性，用单克隆抗IFN-γ抗体（MAb）对其进行处理。使用了两种单克隆抗体：R4-6A2，一种大鼠抗小鼠的中和免疫球蛋白G1，它是针对天然小鼠IFN-γ制备的；以及DB-1，一种针对重组大鼠IFN-γ制备的小鼠抗大鼠免疫球蛋白G1，它既能中和小鼠分子也能中和大鼠分子。C57BL/10ScNH小鼠在感染前1天腹腔注射200微克R4-6A2，并在第21天前每3天注射一次。对照小鼠用正常大鼠血清处理。在单独的实验中，从感染当天开始，给C57BL/10ScNH小鼠腹腔注射DB-1（每周1.0毫克，共4周）；对照小鼠未处理。对照小鼠和用单克隆抗体处理的小鼠腹腔内感染10⁶ 感染查巴迪疟原虫AS的寄生红细胞，并确定感染的过程和结果。对照小鼠的感染过程特征为寄生虫血症峰值在30%至40%的寄生红细胞之间，并且在4周时寄生虫被清除。用单克隆抗体处理的小鼠在寄生虫血症峰值前1至2天表现出明显更高的寄生虫血症，以及明显更高的峰值寄生虫血症，但在4周时也完全清除了感染。因此，这些结果表明用抗IFN-γ单克隆抗体处理会损害但不会完全消除宿主对查巴迪疟原虫AS的抗性。我们还检测了用疟疾抗原或伴刀豆球蛋白A体外培养的脾细胞产生IFN-γ的动力学。在腹腔注射10⁶ 感染查巴迪疟原虫AS的寄生红细胞后的不同时间，从个体C57BL/6小鼠中回收脾细胞。通过酶联免疫吸附测定法定量产生的IFN-γ的量。在每种情况下，IFN-γ产生的峰值恰好在寄生虫血症峰值之前出现，随后在感染后42天内下降到很少或没有IFN-γ产生。因此，感染动物脾细胞体外产生IFN-γ的动力学与寄生虫血症峰值前及峰值时体内对内源分子的需求之间存在平行关系。总之，这些结果表明IFN-γ依赖性和非依赖性机制都有助于宿主对查巴迪疟原虫AS的抗性。
