Kita Yoko, Hashimoto Satomi, Nakajima Toshihiro, Nakatani Hitoshi, Nishimatsu Shiho, Nishida Yasuko, Kanamaru Noriko, Kaneda Yasuhumi, Takamori Yasushi, McMurray David, Tan Esterlina V, Cang Marjorie L, Saunderson Paul, Dela Cruz E C, Okada Masaji
Clinical Research Center; National Hospital Organization Kinki-chuo Chest Medical Center; Kitaku, Sakai Japan.
Hum Vaccin Immunother. 2013 Mar;9(3):526-33. doi: 10.4161/hv.23230. Epub 2012 Dec 18.
Multi-drug resistant tuberculosis (MDR-TB) and extremely drug resistant (XDR) TB are big problems in the world. We have developed novel TB therapeutic vaccines, HVJ-Envelope/HSP65 + IL-12 DNA vaccine (HSP65-vaccine), granulysin vaccine and killer specific secretory protein of 37kDa (Ksp37) vaccine.
HSP65 vaccine showed strong therapeutic effect against both MDR-TB and XDR-TB in mice. Intradermal immunization of HSP65-vaccine showed stronger therapeutic effect against TB than intramuscular or subcutaneous immunization. Furthermore, the synergistic therapeutic effect was observed when the vaccine was administrated in combination with Isoniazid (INH), which is a first line drug for chemotherapy. The combination of types of vaccines (HSP65- and granulysin- vaccines) also showed synergistic therapeutic effect. In the monkey model, granulysin-vaccine prolonged the survival period after the infection of TB and long-term survival was observed in vaccine-treated group. We examined the potential of two kinds of novel DNA vaccines (Ksp37-vaccine and granulysin-vaccine). Both vaccines augmented in vivo differentiation of CTL against TB. We measured the amount of Ksp37 protein in human serum and revealed that the level of Ksp37 protein of patients with tuberculosis was lower than that of healthy volunteers. Therefore, we established Ksp37 transgenic mice as well as granulysin transgenic mice to elucidate the function of those proteins. Both transgenic mice were resistant to TB infection.
These data indicate the potential of combinational therapy; the combination of two DNA vaccines or combination of DNA vaccine with antibiotic drug. Thus, it will provide a novel strategy for the treatment of MDR-TB.
耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）是全球面临的重大问题。我们研发了新型结核病治疗性疫苗，如HVJ-包膜/HSP65 + IL-12 DNA疫苗（HSP65疫苗）、颗粒溶素疫苗和37kDa杀伤特异性分泌蛋白（Ksp37）疫苗。
HSP65疫苗在小鼠体内对MDR-TB和XDR-TB均显示出强大的治疗效果。皮内免疫HSP65疫苗对结核病的治疗效果强于肌肉注射或皮下免疫。此外，该疫苗与一线化疗药物异烟肼（INH）联合使用时观察到协同治疗效果。不同类型疫苗（HSP65疫苗和颗粒溶素疫苗）联合使用也显示出协同治疗效果。在猴模型中，颗粒溶素疫苗延长了结核感染后的生存期，疫苗治疗组观察到长期存活。我们研究了两种新型DNA疫苗（Ksp37疫苗和颗粒溶素疫苗）的潜力。两种疫苗均增强了体内针对结核病的CTL分化。我们检测了人血清中Ksp37蛋白的含量，发现结核病患者的Ksp37蛋白水平低于健康志愿者。因此，我们建立了Ksp37转基因小鼠和颗粒溶素转基因小鼠以阐明这些蛋白的功能。两种转基因小鼠均对结核感染具有抗性。
这些数据表明联合治疗具有潜力；两种DNA疫苗联合或DNA疫苗与抗生素联合。因此，这将为MDR-TB的治疗提供一种新策略。
