Effector and regulatory T cell responses and protection from clinical malaria

效应和调节性 T 细胞反应以及对临床疟疾的保护

• 批准号: 8241914
• 负责人: MARGARET E FEENEY
• 金额: $ 50.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241914
• 关键词: Address; Animal Experiments; Antigens; Antimalarials; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cellular Immunity; Characteristics; Chemoprevention; Chemopreventive Agent; Child; Childhood; Chloroquine; Chronic; Clinical; Clinical Trials; Culicidae; Data; Development; Environmental Exposure; Epidemiology; Erythrocytes; Exposure to; Fostering; Frequencies; Functional disorder; Generations; Goals; Hepatocyte; Human; Immune; Immune response; Immunity; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infant; Infection; Intervention; Life; Liver; Longitudinal Studies; Malaria; Malaria Vaccines; Mediating; Mus; Natural Immunity; Parasitemia; Parasites; Participant; Phase; Phenotype; Plasmodium falciparum; Positioning Attribute; Preventive; Prophylactic treatment; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recurrence; Regimen; Regulatory T-Lymphocyte; Relative (related person); Role; Safety; Sampling; Sporozoites; Staging; Sterility; Subunit Vaccines; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Uganda; Vaccines; base; comparative efficacy; exhaust; infancy; prevent; prospective; public health relevance; research study; response; transmission process

DESCRIPTION (provided by applicant): Each year, malaria claims the lives of over a million individuals, mostly young children. An effective malaria vaccine is urgently needed, but progress toward this goal has been hindered by our limited understanding of the mechanisms underlying natural immunity to malaria and a lack of reliable in vitro correlates of protection. Data from both human and animal experiments offer hope that vaccine-mediated induction of immunity to malaria is achievable. Infection with irradiated sporozoites, which arrest development during the liver stage, confers sterile protective immunity in humans, suggesting an important role for the T cell response to pre-erythrocytic antigens. Importantly, studies in mice and more recently in humans demonstrate that similar protection is conferred by non-attenuated parasites when given under cover of chloroquine, which prevents blood stage malaria but does not impact the liver stage. Together these data indicate that limiting exposure to blood stage infection may actually enhance the development of immune responses to pre-erythrocytic stages, perhaps by avoiding the immunosuppressive mechanisms induced by parasitemia. The proposed study will leverage samples to be collected as part of a randomized clinical trial based in Tororo, Uganda that will compare the efficacy and safety of 3 promising malaria chemopreventive strategies with the current standard of no chemoprevention. This trial provides a unique opportunity to study the impact of chemoprevention, which uncouples liver-stage and blood-stage malaria, on the malaria-specific immune response to natural infection among infants in a high transmission setting. We will test the hypothesis that selective suppression of erythrocytic stage malaria by chemoprevention will enhance the development of highly functional T cell responses targeting pre-erythrocytic antigens and limit the induction of immunosuppressive mechanisms, and will thus foster the development of protective antimalarial immunity. In the first aim, we will prospectively evaluate the impact of potent chemoprevention on the development of the adaptive T cell response to P. falciparum during infancy. The frequency, breadth, and functional attributes of CD4 and CD8 T cells targeting pre-erythrocytic and erythrocytic stage P. falciparum antigens will be compared longitudinally between children randomized to receive chemoprevention vs. no intervention. In the second aim, we will assess the impact of recurrent parasitemia on the development of immune suppressor mechanisms and T cell dysfunction. We hypothesize that immune regulatory mechanisms, including Foxp3+ regulatory CD4 T cells, are induced by parasitemia and interfere with the establishment of effective, durable malaria-specific T cell responses that are necessary for protective immunity. In the third aim, we will determine whether malaria-specific T cell responses and/or immune suppressor mechanisms are associated with prospective protection from malaria following cessation of chemoprevention, following adjustment for epidemiologic covariates of exposure. These studies will greatly enhance our understanding of the acquisition of natural immunity to malaria in infancy. PUBLIC HEALTH RELEVANCE: Malaria is a leading killer of children worldwide, but efforts to develop a preventive vaccine have failed due to our poor understanding of the immune response to infection by malaria parasites. We will perform detailed longitudinal studies of the immune response to malaria in Ugandan infants participating in a clinical trial of chemoprevention strategies. The immune responses of children receiving chemoprevention, which prevents blood-stage but not liver-stage malaria, will be compared to children who do not receive chemoprevention, and these immune parameters will be correlated with prospective protection from clinical malaria following cessation of chemoprevention

描述（由申请人提供）：每年，疟疾宣称超过一百万个人（主要是年幼的孩子）的生命。迫切需要一种有效的疟疾疫苗，但是我们对疟疾自然免疫的机制的有限理解阻碍了朝着这一目标朝着这一目标方面的进步，并且缺乏可靠的保护性保护相关性。来自人类和动物实验的数据提供了希望，可以实现疫苗介导的对疟疾免疫的诱导。在肝脏阶段停止发育的辐照孢子虫感染，赋予了人类无菌保护性免疫，这表明T细胞对蜂囊前抗原的反应起着重要作用。重要的是，对小鼠和人类进行的研究表明，在氯喹的覆盖范围内给予非销售的寄生虫，从而防止血液阶段疟疾，但不会影响肝脏阶段。总之，这些数据表明，限制暴露于血液阶段感染实际上可能会增强对肉毒前阶段的免疫反应的发展，也许是通过避免寄生虫血症引起的免疫抑制机制。拟议的研究将利用样本作为基于乌干达Tororo的随机临床试验的一部分收集的样本，该试验将比较3种有希望的疟疾化学预防策略的功效和安全性与当前无化学预防的标准。该试验为研究化学预防的影响提供了一个独特的机会，该化学预防的影响（未取消肝脏阶段和血液阶段疟疾对疟疾特异性免疫反应对较高传播环境中婴儿自然感染的反应。我们将检验以下假设：通过化学预防选择性抑制红细胞疟疾将增强针对肉眼性抗细胞前抗原的高功能性T细胞反应的发展，并限制免疫抑制机制的诱导，从而促进保护性抗解性免疫的发展。在第一个目标中，我们将前瞻性评估有效的化学预防对婴儿期在婴儿期对恶性疟原虫反应的发展的影响。 CD4和CD8 T细胞的频率，广度和功能属性将在儿童之间随机进行化学预防与无干预的儿童之间进行纵向比较。在第二个目标中，我们将评估复发性寄生虫血症对免疫抑制机制和T细胞功能障碍发展的影响。我们假设免疫调节机制（包括FoxP3+调节性CD4 T细胞）是由寄生虫病诱导的，并干扰了为保护性免疫所必需的有效，耐用的疟疾特异性T细胞反应的建立。在第三个目的中，我们将确定疟疾特异性的T细胞反应和/或免疫抑制机制是否与预防停止后的前瞻性保护免受疟疾的保护有关，此前调整了暴露的流行病学协变量。这些研究将极大地增强我们对婴儿自然免疫的获取的理解。 公共卫生相关性：疟疾是全球儿童的主要杀手，但是由于我们对疟疾寄生虫感染的免疫反应的不良理解，开发预防性疫苗的努力失败了。我们将对参加化学预防策略的临床试验的乌干达婴儿的免疫反应进行详细的纵向研究。接受化学预防的儿童的免疫反应（防止血液阶段但不能进行肝阶段疟疾）与未接受化学预防的儿童进行比较，并且这些免疫参数将与预防性暂停化学预防后的临床疟疾的前瞻性保护相关。