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

细胞因子刺激的 NK 细胞可预防小鼠脑型疟疾

• 批准号: 9120223
• 负责人: Kristina Stoermer Burrack
• 金额: $ 5.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9120223
• 关键词: Adoptive Transfer; Antibodies; Antimalarials; Automobile Driving; Binding; Brain; C57BL/6 Mouse; CD8B1 gene; Cells; Cerebral Malaria; Cerebrovascular system; Cessation of life; Child; Chimeric Proteins; Clinical; Complex; Complication; Cytokine Receptors; Data; Development; Disease; Drug resistance; Erythrocytes; Family; Foundations; Human; Immune; Immune response; Immune system; Infection; Inflammatory; Inflammatory Response; Interferon Type II; Interleukin-15; Interleukin-2; Intervention; Investigation; Knowledge; Laboratories; Leukocytes; Lymphocyte Activation; Malaria; Measures; Mediating; Modeling; Mouse Strains; Mus; NK Cell Activation; Natural Killer Cells; Parasites; Pathogenesis; Pathologic; Pathology; Pathway interactions; Plasmodium; Plasmodium berghei; Population; Process; Production; Property; Research; Resistance; Severity of illness; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Vascular Endothelial Cell; Viral; base; cell type; combat; cytokine; global health; human disease; immune activation; immunopathology; immunoregulation; innovation; insight; killings; malaria infection; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pathogen; perforin; prevent; protective effect; public health relevance; receptor; response; therapeutic target; tumor

 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.

 描述(申请人提供)：疟疾是一个破坏性的全球卫生问题，抗药性寄生虫的出现加剧了这一问题。因此，需要免疫干预等新的方法来抗击疟疾。这种疾病最严重的并发症是脑型疟疾(CM)，每年导致约100万人死亡，主要是幼儿。用伯氏疟原虫感染易感小鼠品系C57BL/6(P.B.Anka)概括了人类疾病的许多方面，并已进行研究，以确定免疫系统的哪些组成部分对CM的发展负责。许多研究表明，过度的免疫激活--包括强烈的促炎细胞因子的产生和T细胞的激活--是致死性CM的驱动因素。因此，找出预防或干预免疫介导的病理的方法将限制这种疾病的严重程度，并可能限制其他免疫病理疾病。本申请中提供的初步数据表明，用IL-15复合体(IL-15C；IL-15与IL-15Ra-Fc融合蛋白结合)治疗C57BL/6小鼠可完全阻断P.B.ANKA诱导的致死性脑炎性疾病，而IL-2复合体(IL-2C；IL-2与抗IL-2S4B6抗体结合)治疗不能。IL-15C和IL-2C通过相同的受体组分传递信号，诱导CD8T细胞和NK细胞的增殖。有趣的是，我们观察到IL-15C处理的NK细胞在这个模型中对CM的保护是必不可少的。此外，用IL-15C(但不是IL-2C)处理的NK细胞过继转移足以阻止CM的诱导，这表明这个NK细胞群主要预防这种致命的疾病。这些数据确定了IL-15和IL-2激活淋巴细胞之间的新区别。因此，我们假设IL-15C处理产生了一个保护性的NK细胞群，不同于IL-2C处理的NK细胞。在目标1中，表型和功能分析将在IL-15C或IL-2C治疗后进行，无论是否有P.B.ANKA感染，描述细胞因子复合体治疗产生的特异性差异，并确定IL-15C处理的NK细胞预防CM发展所需的机制(S)。具体地说，我们认为IL-15C刺激的NK细胞抑制病理性T细胞反应，从而对CM具有保护作用。因此，AIM 2将评估经IL-15C处理的NK细胞对T细胞的免疫调节特性，重点检测NK细胞对T细胞的杀伤和抑制作用。总而言之，拟议的研究将表征以前未被认识到的IL-15C和IL-2C激活NK细胞之间的区别，并极大地扩大我们对细胞因子复合疗法在感染存在和不存在时的影响的了解。此外，这些研究将对 IL-15C处理的NK细胞介导的CM控制的基础。从机制上了解CM的发病机制和细胞因子复合体的扰动过程，将为确定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疾病的创新策略。