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Role of CD4 T cell inhibitor receptors during Plasmodium blood stage infection

CD4 T 细胞抑制剂受体在疟原虫血期感染过程中的作用

基本信息

批准号：
8607494
负责人：
Noah Sullivan Butler
金额：
$ 10.8万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-18 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607494
关键词：
Acute Address Africa South of the Sahara Antibodies Antibody Formation Antimalarials B-Lymphocytes Blood CD4 Positive T Lymphocytes Cells Cellular Structures Cessation of life Characteristics Child Childhood Clinical Data Development Disease Drug Targeting Epitopes Exhibits Functional disorder Funding Future Goals Host Defense Mechanism Human Immune response Immune system Immunity Immunoglobulins Immunologic Techniques Immunologics Immunology Infection K22 Award Knowledge Laboratories Licensing Life Ligands Link MHC antigen Malaria Methodology Mus Nature Parasite Control Parasite resistance Parasitemia Parasites Pharmaceutical Preparations Phenotype Plasmodium Plasmodium falciparum Plasmodium yoelii Production Public Health Reporting Resistance Resolution Resources Risk Rodent Model Role Staging Surface T cell response T-Lymphocyte T-Lymphocyte Epitopes Therapeutic Translations United States National Institutes of Health Up-Regulation Vaccine Design Vaccines Virus Diseases adaptive immunity base clinically relevant combinatorial cytokine exhaustion experience fight against inhibitor/antagonist insight mortality novel novel strategies novel vaccines programs public health relevance receptor response weapons

项目摘要

DESCRIPTION (provided by applicant): Plasmodium infection exacts a significant toll on human public health. More than 3.3 billion people are at risk for exposure and >250 million new cases of malaria are reported each year. Much effort has been directed towards developing immunologic strategies that target the clinically relevant blood stage of Plasmodium infection, but to date no licensed vaccines exist. In rodent models of Plasmodium blood stage infection, parasite-specific CD4 T cells have been shown to be necessary for protection. In humans, the presence of parasite-specific CD4 T cells correlates with resistance to severe disease. Importantly, the precise characteristics of protective CD4 T cell responses (numbers, phenotype, functional attributes) remain largely unknown. The candidate has recently developed and applied a novel surrogate activation marker approach to track the total, parasite-specific CD4 T cell response during Plasmodium blood infection in mice, without a priori knowledge of parasite antigens, MHC restriction or epitopes. [Using this approach, the candidate has determined that Plasmodium yoelii blood stage infection results in sustained expression of multiple inhibitory receptors on responding T cells and that these cells exhibit impaired cytokine production, demonstrating that these T cells have undergone functional exhaustion during prolonged malaria. Moreover, therapeutically blocking the functional engagement of at least two inhibitor receptors with their ligands in mice with established malaria results in immediate contro of parasite replication and enhanced parasite clearance. Finally, the candidate has determined that inhibitory receptor blockade has major impacts on both parasite-specific CD4 and B cell/antibody responses during blood stage Plasmodium infection. These new results provide the necessary rationale for the proposed studies to dissect the cellular and humoral basis for enhanced parasite clearance following therapeutic inhibitory receptor blockade in mice with established clinical malaria.] The candidate has more than 10 years of experience with immunologic techniques and approaches relevant to this application. The K22 award will provide the resources necessary to advance the candidate's goal of successfully establishing an NIH R01- funded, independent laboratory to study in detail the quantitative and qualitative features of Plasmodium- specific CD4 T cell and B cell/antibody responses. Collectively, by virtue of the candidate's new approaches and methodologies, the studies detailed herein will provide critical insight into the features of anti-Plasmodial adaptive immunity that determine protection, which will impact current and future therapies and approaches to vaccine design in the context of Plasmodium infection. )

描述（由申请人提供）：疟原虫感染对人类公共卫生造成重大损失。超过 33 亿人面临感染风险，每年报告的疟疾新病例超过 2.5 亿例。人们付出了很多努力来开发针对疟原虫感染的临床相关血液阶段的免疫策略，但迄今为止还没有获得许可的疫苗。在疟原虫血期感染的啮齿动物模型中，寄生虫特异性 CD4 T 细胞已被证明是保护所必需的。在人类中，寄生虫特异性 CD4 T 细胞的存在与对严重疾病的抵抗力相关。重要的是，保护性 CD4 T 细胞反应的精确特征（数量、表型、功能属性）仍然很大程度上未知。该候选人最近开发并应用了一种新型替代激活标记方法，用于追踪小鼠疟原虫血液感染期间寄生虫特异性 CD4 T 细胞的总体反应，而无需事先了解寄生虫抗原、MHC 限制或表位。 [利用这种方法，候选人确定约氏疟原虫血期感染会导致应答 T 细胞上多种抑制性受体的持续表达，并且这些细胞表现出细胞因子产生受损，这表明这些 T 细胞在长期疟疾期间经历了功能衰竭。此外，在患有疟疾的小鼠中，通过治疗性阻断至少两种抑制剂受体与其配体的功能性结合，可以立即控制寄生虫复制并增强寄生虫清除率。最后，候选人确定抑制性受体阻断对血液阶段疟原虫感染期间寄生虫特异性 CD4 和 B 细胞/抗体反应具有重大影响。这些新结果为拟议的研究提供了必要的理论基础，以剖析在已确诊的临床疟疾小鼠中治疗性抑制性受体阻断后增强寄生虫清除的细胞和体液基础。]该候选人在与此应用相关的免疫技术和方法方面拥有超过 10 年的经验。 K22 奖将提供必要的资源，以推进候选人成功建立 NIH R01 资助的独立实验室的目标，以详细研究疟原虫特异性 CD4 T 细胞和 B 细胞/抗体反应的定量和定性特征。总的来说，凭借候选者的新方法和方法，本文详细的研究将为决定保护作用的抗疟原虫适应性免疫的特征提供重要的见解，这将影响当前和未来的疟原虫感染背景下的疗法和疫苗设计方法。）