Study on the role of IL-12 in protective immunity against infection

本研究利用致死性伯氏疟原虫NK 65株及其辐射诱导的自限性伯氏疟原虫XAT株研究了IL-12在宿主对血期疟疾感染的抗性发展中的作用，发现伯氏疟原虫XAT感染诱导了脾脏中IL-12的表达和IFN-γ的产生，这在宿主抗性的形成中起重要作用。另一方面，伯氏疟原虫NK 65感染还诱导脾和肝中IL-12表达和由此产生的IFN-γ产生，这对于发病机制是相当重要的。此外，已经显示，位于IL-12和IFN-γ下游的NK细胞和NO参与宿主对伯氏疟原虫XAT感染的抗性并不重要，尽管自限性菌株的感染诱导了比致死性菌株更高的NK细胞裂解活性和NO产生。已经揭示了涉及主要由CD 4 ^# T细胞产生的IFN-γ的其他机制对于宿主抗性是重要的，并且仍有待阐明。似乎有两种机制涉及IFN-γ，并在感染的早期和晚期发挥作用。一种是非特异性保护，另一种是抗体依赖性Fc受体介导的吞噬作用或ADCC，这些潜在的机制目前正在研究中。我们还试图建立一种有效的方法来诱导针对疟疾肝期感染的保护性免疫，制备了表达约氏疟原虫和恶性疟原虫CS蛋白的各种重组病毒，并比较了它们产生抗CS蛋白特异性CD 8 ^+ T细胞的效力。重组腺病毒的单次免疫和重组流感病毒的初免，然后用重组牛痘病毒加强免疫，已显示可有效诱导CD 8 ^+ T细胞介导的抗疟疾保护性免疫，这表明这些是非常有效的抗疟疾感染的疫苗接种方式。

We have investigated the role of IL-12 in the development of host resistance to the bloodstage malaria infection and also in the pathogenesis using a lethal strain P.berghei NK65 and its irradiation-induced self-limiting strainP.berghei XAT.The P.berghei XAT infection induced IL-12 expression and resultant IFN-gamma production in spleen, which are important for the host resistance. On the other hand, the P.berghei NK65 infection also induced IL-12 expression and resultant IFN-gamma production in spleen and liver, which are rather important for the pathogenesis. Furthermore, the involvement of NK cells and NO, which are located downstream IL-12 and IFN-gamma, in the host resistance to P.berghei XAT infection has been shown not to be important although the infection with the self-limiting strain induced higher NK cell lytic activity and production of NO than that with the lethal strain. Other mechanism(s) involving IFN-gamma mainly produced by CD4^# T cells has been revealed to be important for the host resistance and remains to be elucidated. There seem to be two mechanisms which involves IFN-gamma and are functioning in early and late phases of the infection. One should be non-specific protection and another should be Ab-dependent Fc receptor-mediated phagocytosis or ADCC.These potential mechanisms are currently under investigation. We also have been trying to create an efficient way to induce the protective immunity to the liver-stage malaria infection, generated various recombinant viruses expressing CS proteins of P.yoelii or P.falciparum and compared their efficacy to produce anti-CS protein specific CD8^+ T cells. Single immunization of the recombinant adenovirus and priming with the recombinant influenza virus followed by a booster with the recombinant vaccinia virus have been shown to efficiently induce CD8^+ T cellmediated protective immunity against malaria, suggesting that these are very efficient way of vaccination against malaria infection.