Derrick Steven C, Repique Charlene, Snoy Philip, Yang Amy Li, Morris Sheldon
Laboratory of Mycobacterial Diseases and Cellular Immunology. Division of Veterinary Services, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892, USA.
Infect Immun. 2004 Mar;72(3):1685-92. doi: 10.1128/IAI.72.3.1685-1692.2004.
Tuberculosis (TB) is the most common opportunistic disease and a potentially fatal complication among immunocompromised individuals infected with human immunodeficiency virus (HIV). Effective vaccination against TB in persons with HIV has been considered unlikely because of the central role that CD4 cells play in controlling tuberculous infections. Here we show that the vaccination of CD8(-/-) mice with a TB DNA vaccine cocktail did not significantly enhance protective responses to a Mycobacterium tuberculosis infection. In contrast, immunization with a DNA vaccine cocktail or with the current TB vaccine, Mycobacterium bovis BCG, induced considerable antituberculosis protective immunity in immune-deficient mice lacking CD4 cells. In vaccinated CD4(-/-) animals, substantially reduced bacterial burdens in organs and much improved lung pathology were seen 1 month after an aerogenic M. tuberculosis challenge. Importantly, the postchallenge mean times to death of vaccinated CD4(-/-) mice were significantly extended (mean with DNA cocktail, 172 +/- 7 days; mean with BCG, 156 +/- 22 days) compared to that of naïve CD4(-/-) mice (33 +/- 6 days). Furthermore, the treatment of DNA-vaccinated CD4(-/-) mice with an anti-CD8 or anti-gamma interferon (IFN-gamma) antibody significantly reduced the effect of immunization, and neither IFN-gamma(-/-) nor tumor necrosis factor receptor-deficient mice were protected by DNA immunization; therefore, the primary vaccine-induced protective mechanism in these immune-deficient mice likely involves the secretion of cytokines from activated CD8 cells. The substantial CD8-mediated protective immunity that was generated in the absence of CD4 cells suggests that it may be possible to develop effective TB vaccines for use in HIV-infected populations.
结核病（TB）是感染人类免疫缺陷病毒（HIV）的免疫功能低下个体中最常见的机会性疾病和潜在致命并发症。由于CD4细胞在控制结核感染中起核心作用，因此一直认为对HIV感染者进行有效的结核病疫苗接种不太可能。在此，我们表明用结核DNA疫苗混合物对CD8（-/-）小鼠进行疫苗接种并不能显著增强对结核分枝杆菌感染的保护性反应。相比之下，用DNA疫苗混合物或当前的结核病疫苗牛分枝杆菌卡介苗（Mycobacterium bovis BCG）进行免疫接种，可在缺乏CD4细胞的免疫缺陷小鼠中诱导出相当程度的抗结核保护性免疫。在经空气传播的结核分枝杆菌攻击1个月后，在接种疫苗的CD4（-/-）动物中，可见器官中的细菌负荷大幅降低，肺部病理状况明显改善。重要的是，与未接种疫苗的CD4（-/-）小鼠（33±6天）相比，接种疫苗的CD4（-/-）小鼠攻击后平均死亡时间显著延长（DNA混合物组平均为172±7天；卡介苗组平均为156±22天）。此外，用抗CD8或抗γ干扰素（IFN-γ）抗体治疗接种DNA疫苗的CD4（-/-）小鼠可显著降低免疫效果，并且IFN-γ（-/-）小鼠和肿瘤坏死因子受体缺陷小鼠均未通过DNA免疫得到保护；因此，在这些免疫缺陷小鼠中，疫苗诱导的主要保护机制可能涉及活化的CD8细胞分泌细胞因子。在没有CD4细胞的情况下产生的大量由CD8介导的保护性免疫表明，有可能开发出用于HIV感染人群的有效结核病疫苗。
