Okada Masaji, Kita Yoko, Nakajima Toshihiro, Kanamaru Noriko, Hashimoto Satomi, Nagasawa Tetsuji, Kaneda Yasufumi, Yoshida Shigeto, Nishida Yasuko, Nakatani Hitoshi, Takao Kyoko, Kishigami Chie, Nishimatsu Shiho, Sekine Yuki, Inoue Yoshikazu, Matsumoto Makoto, McMurray David N, De la Cruz E C, Tan E V, Abalos R M, Burgos J A, Saunderson Paul, Sakatani Mitsunori
Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center, Kitaku, Sakai, Osaka, Japan.
Hum Vaccin. 2011 Jan-Feb;7 Suppl:60-7. doi: 10.4161/hv.7.0.14563.
Multi-drug resistant (MDR) Mycobacterium Tuberculosis (M.TB) is a big problem in the world. We have developed novel TB therapeutic vaccines.
DNA vaccine expressing mycobacterial heat shock protein 65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. M. TB, MDR-TB or extremenly drug resistant (XDR-TB) was injected i.v. into DBA/1 mice, and treated with the vaccine three times. This HVJ-E/Hsp65DNA+IL-12DNA vaccine provided strong therapeutic efficacy against MDR-TB and XDR-TB (prolongation of survival time and the decrease in the number of TB) in mice. Therapeutic effect of this vaccine on TB infection was also demonstrated in chronic TB infection murine model using aerosol infection intratracheally. On the other hand, granulysin protein produced from CTL has lethal activity against TB. Granulysin protein vaccine also exerted strong therapeutic effect. Furthermore, we extended our studies to monkey model, which is currently the best animal model of human TB. Hsp65DNA+IL-12 DNA vaccine exerted strong therapeutic efficacy (100% survival and augmentation of immune responses) in the TB-infected monkeys. In contrast, the survival of the saline control group was 60% at 16 week post-challenge. HVJ-Envelope/HSP65 DNA+IL-12 DNA vaccine increased the body weight of TB-infected monkeys, improved the erythrocyte sedimentation rate, and augmentated the immune responses (proliferation of PBL and IL-2 production). The enhancement of IL-2 production from monkeys treated with this vaccine was correlated with the therapeutic efficacy of the vaccine.
These data indicate that novel vaccines might be useful against TB including XDR-TB and MDR-TB for human therapeutic clinical trials.
耐多药结核分枝杆菌（MDR - M.TB）是全球面临的一个重大问题。我们研发了新型结核病治疗性疫苗。
表达分枝杆菌热休克蛋白65和白细胞介素 - 12的DNA疫苗通过日本血凝病毒（HVJ）包膜递送。将结核分枝杆菌、耐多药结核分枝杆菌或广泛耐药结核分枝杆菌（XDR - TB）静脉注射到DBA/1小鼠体内，并用该疫苗治疗三次。这种HVJ - E/Hsp65DNA + IL - 12DNA疫苗对小鼠的耐多药结核分枝杆菌和广泛耐药结核分枝杆菌具有强大的治疗效果（延长生存时间并减少结核数量）。在经气管内气溶胶感染的慢性结核感染小鼠模型中也证明了该疫苗对结核感染的治疗作用。另一方面，细胞毒性T淋巴细胞产生的颗粒溶素蛋白对结核具有致死活性。颗粒溶素蛋白疫苗也发挥了强大的治疗作用。此外，我们将研究扩展到猴模型，这是目前人类结核病的最佳动物模型。Hsp65DNA + IL - 12 DNA疫苗在感染结核的猴子中发挥了强大的治疗效果（100%存活并增强免疫反应）。相比之下，生理盐水对照组在攻击后16周的存活率为60%。HVJ - 包膜/HSP65 DNA + IL - 12 DNA疫苗增加了感染结核的猴子的体重，改善了红细胞沉降率，并增强了免疫反应（外周血淋巴细胞增殖和白细胞介素 - 2产生）。用该疫苗治疗的猴子白细胞介素 - 2产生的增强与疫苗的治疗效果相关。
这些数据表明，新型疫苗可能对包括广泛耐药结核分枝杆菌和耐多药结核分枝杆菌在内的结核病用于人类治疗性临床试验有用。
