Protection from cerebral malaria in mice by cytokine-stimulated NK cells

 描述（由申请人提供）：疟疾是一个毁灭性的全球健康问题，由于抗药性寄生虫的出现而加剧。因此，需要采取免疫干预等防治疟疾的新办法。这种疾病最严重的并发症是脑型疟疾（CM），每年造成约100万人死亡，主要是幼儿。用伯氏疟原虫ANKA（P.b. ANKA）概括了人类疾病的许多方面，并已被研究以确定免疫系统的哪些成分是导致CM发展的原因。许多研究表明，过度的免疫激活-包括强大的促炎细胞因子产生和T细胞激活-是致命CM的驱动因素。因此，确定预防或干预免疫介导的病理学的方法将限制这种疾病和潜在的其他免疫病理学疾病的严重程度。 本申请中提供的初步数据鉴定了用IL-15复合物（IL-15 C; IL-15结合IL-15 Ra-Fc融合蛋白）处理C57 BL/6小鼠完全阻断了P. b. ANKA诱导的致命性脑炎性疾病，而用IL-2复合物（IL-2C; IL-2结合抗IL-2 S4 B6抗体）治疗则没有。IL-15 C和IL-2C通过相同的受体组分发出信号，并诱导CD 8 T细胞和NK细胞的扩增。有趣的是，我们观察到IL-15 C处理的NK细胞对于在该模型中针对CM的保护是必需的。此外，用IL-15 C（而不是IL-2C）处理的NK细胞的过继转移足以防止CM诱导，表明该NK细胞群体主要保护免于这种致命性疾病。这些数据确定了IL-15和IL-2对淋巴细胞活化的新区别。因此，我们假设IL-15 C处理产生与IL-2C处理的NK细胞不同的保护性NK细胞群体。在目标1中，将在IL-15 C或IL-2C治疗（伴或不伴P. b）后进行表型和功能分析。ANKA感染，以描述细胞因子复合物治疗产生的特异性差异，并确定IL-15 C处理的NK细胞预防CM发展所需的机制。具体而言，我们建议IL-15 C刺激的NK细胞抑制病理性T细胞反应，从而保护CM。因此，目标2将评估IL-15 C处理的NK细胞对T细胞的免疫调节特性，特别强调检查NK细胞可以对T细胞发挥的细胞溶解和抑制作用。 总的来说，拟议的调查将表征以前未被赞赏的区别NK细胞激活的IL-15 C和IL-2C，并大大扩展了我们的知识的影响，细胞因子复合物治疗的存在和不存在的感染。此外，这些研究将产生新的见解， IL-15 C处理的NK细胞介导的CM控制的基础。对CM发病机制和细胞因子复合物扰动过程的机制理解将为识别新的治疗靶点提供重要基础，并有助于开发有效治疗严重疟疾和潜在其他免疫病理学疾病的创新策略。

 DESCRIPTION (provided by applicant): Malaria is a devastating global health problem that has been exacerbated by the emergence of drug- resistant parasites. Thus, new approaches to combat malaria such as immune interventions are needed. The most severe complication of this disease is cerebral malaria (CM), which causes around a million deaths annually, mainly in young children. Infection of susceptible mouse strains such as C57BL/6 with Plasmodium berghei ANKA (P.b. ANKA) recapitulates many aspects of the human disease and has been studied to identify which components of the immune system are responsible for the development of CM. A number of studies have demonstrated that excessive immune activation - including robust proinflammatory cytokine production and T cell activation - is the driver of lethal CM. Thus, identifying ways to prevent or intervene in the immune-mediated pathology would limit the severity of this disease and potentially other immunopathologic diseases. Preliminary data presented in this application identifies that treatment with of C57BL/6 mice with IL-15 complexes (IL-15C; IL-15 bound to an IL-15Ra-Fc fusion protein) completely blocked P.b. ANKA-induced fatal brain inflammatory disease, while treatment with IL-2 complexes (IL-2C; IL-2 bound to the anti-IL-2 S4B6 antibody) did not. Il-15C and IL-2C signal through the same receptor components and induce expansion of both CD8 T cells and NK cells. Intriguingly, we observed that IL-15C-treated NK cells were essential for protection against CM in this model. Furthermore, adoptive transfer of NK cells treated with IL-15C (but not IL-2C) was sufficient to prevent CM induction, suggesting that this NK cell population dominantly protects against this fatal disease. These data identify a novel distinction between lymphocyte activation by IL-15 and IL-2. Thus, we hypothesize that IL-15C treatment generates a protective NK cell population distinct from IL-2C-treated NK cells. In Aim 1, phenotypic and functional analyses will be performed following IL-15C or IL-2C treatment, with or without P.b. ANKA infection, to delineate the specific differences generated by cytokine complex treatment and determine the mechanism(s) required by IL-15C-treated NK cells to prevent the development of CM. Specifically, we propose that IL-15C-stimulated NK cells inhibit the pathologic T cell response, resulting in protection from CM. Hence, Aim 2 will assess the immunoregulatory properties of IL-15C-treated NK cells on T cells with a specific emphasis on examining the cytolytic and inhibitory effect NK cells can exert on T cells. Collectively, the proposed investigations will characterize the previously unappreciated distinction between NK cell activation by IL-15C and IL-2C and greatly expand our knowledge of the effects of cytokine complex therapy in the presence and absence of an infection. In addition, these studies will yield novel insights into the basis for the IL-15C-treated NK cell-mediated control of CM. A mechanistic understanding of CM pathogenesis and the process of cytokine complex perturbation will provide an important foundation for the identification of new therapeutic targets and aid in the development of innovative strategies for effectively treating severe malaria and potentially other immunopathologic diseases.