Immunologic consequences of highly effective antimalarial chemoprevention

高效抗疟化学预防的免疫学后果

基本信息

批准号：
8463455
负责人：
Prasanna Jagannathan
金额：
$ 13.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463455
关键词：
2 year old Address Adult Africa South of the Sahara African Animals Anti-malarial drug resistance Antigens Antimalarials Area Artemisinins Award Biological Assay Blood CD4 Positive T Lymphocytes California Cells Cessation of life Chemoprevention Child Childhood Clinical Clinical Research Clinical Trials Combined Modality Therapy Communicable Diseases Data Development Effectiveness Ensure Epidemiologist Erythrocytes Exposure to Flow Cytometry Funding Future Generations Goals Grant HIV Hepatocyte Human Immune Immune response Immunity Immunologics Immunology In Vitro Incidence Individual Infant Infection Interleukin-10 International Intervention Life Malaria Mediating Mentored Patient-Oriented Research Career Development Award Mentors Messenger RNA Modality Morbidity - disease rate Mus Outcome Parasites Parasitic infection Parasitology Parents Plasma Plasmodium falciparum Population Positioning Attribute Production Randomized Randomized Clinical Trials Research Research Design Research Personnel Resources Risk Sampling San Francisco Sporozoites Staging T cell response T-Lymphocyte Testing Training Uganda United States National Institutes of Health Universities Vaccines arm artemisinine base burden of illness career development cytokine design immunopathology improved longitudinal analysis mortality multidisciplinary patient oriented prevent programs randomized trial response skills translational study

项目摘要

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Prasanna Jagannathan, a fellow in infectious diseases at the University of California at San Francisco who is establishing himself as a young investigator in patient-oriented, field-based studies of antimalarial immunity. This K23 award will provide Dr. Jagannathan with the support necessary to accomplish the following goals: (1) to study the impact of antimalarial chemoprevention on the development of IL-10-specific counterregulatory mechanisms and malaria-specific T cell responses in children living in high endemicity settings, and (2) to determine whether these responses correlate with protection from subsequent malaria. To achieve these goals, Dr. Jagannathan has assembled a mentoring team comprised of a primary mentor, Dr. Margaret Feeney, an expert in pediatric translational immunologic research in infectious diseases, and three co-mentors: Dr. Grant Dorsey, a malaria epidemiologist and PI of the parent clinical trial from which samples for this K23 will be obtained; Dr. Philip Rosenthal, a expert in malaria parasitology and antimalarial drug resistance; and Dr. Diane Havlir, an international leader of clinical research in HIV, TB, and malaria. Antimalarial chemoprevention is an emerging modality to prevent deaths and morbidity from malaria in children living in highly endemic areas, but there are concerns that it will delay the acquisition of antimalarial immunity. Recent studies in mice and humans have challenged this paradigm, and suggest that selective blockade of blood stage infection with antimalarial drugs may paradoxically enhance the development of sterilizing antimalarial immunity. Leveraging samples from an ongoing, NIH-funded randomized clinical trial of antimalarial chemoprevention in African children, Dr. Jagannathan will test the central hypothesis that chemoprevention suppresses the generation of IL-10 mediated counterregulatory mechanisms and allows for the development of polyfunctional malaria-specific CD4+ T cell responses. Specifically, he will compare IL-10 production by T cells and other immune cell populations (Aim 1) and malaria-specific T cell responses to whole parasite antigens using multiparameter flow cytometry (Aim 2) in children randomized to receive effective malaria chemoprevention or no chemoprevention. In the third aim, he will conduct a within-group analysis of the association between IL-10 production and malaria-specific T cell responses, and whether these responses are subsequently associated with reductions in the future incidence of malaria. Through a focused program of mentored training and coursework, the candidate will develop advanced skills in translational immunology, clinical research design, and the conduct of translational studies of malaria in resource-limited settings. At the completion of this award, Dr. Jagannathan will be well positioned to develop an R01 application to further define correlates and mechanisms of protective immunity to malaria.

描述（由申请人提供）：这是一份为 Prasanna Jagannathan 博士申请 K23 奖的申请，Prasanna Jagannathan 博士是加州大学旧金山分校传染病研究员，正在将自己定位为以患者为导向、基于现场的年轻研究者抗疟免疫研究。该 K23 奖项将为 Jagannathan 博士提供实现以下目标所需的支持：(1) 研究抗疟化学预防对生活在儿童中的 IL-10 特异性反调节机制和疟疾特异性 T 细胞反应的影响高流行地区；(2) 确定这些反应是否与预防随后的疟疾相关。为了实现这些目标，Jagannathan 博士组建了一个指导团队，其中包括一位主要导师 Margaret Feeney 博士（传染病儿科转化免疫学研究专家）和三位联合导师：Grant Dorsey 博士（疟疾流行病学家和从中获得该 K23 样本的母体临床试验的 PI； Philip Rosenthal博士，疟疾寄生虫学和抗疟药物耐药性专家；黛安·哈夫利尔 (Diane Havlir) 博士是艾滋病毒、结核病和疟疾临床研究的国际领导者。抗疟化学预防是一种新兴的方法，旨在预防生活在高流行地区的儿童因疟疾死亡和发病，但有人担心这会延迟抗疟免疫的获得。最近对小鼠和人类的研究对这一范式提出了挑战，并表明用抗疟药物选择性阻断血液阶段感染可能会反而增强杀菌性抗疟免疫的发展。 Jagannathan 博士将利用来自 NIH 资助的非洲儿童抗疟化学预防随机临床试验的样本，测试化学预防抑制 IL-10 介导的反调节机制的产生并允许多功能疟疾特异性 CD4+ 发展的中心假设。 T 细胞反应。具体来说，他将使用多参数流式细胞术比较随机接受有效疟疾化学预防或不接受有效疟疾化学预防的儿童中 T 细胞和其他免疫细胞群产生的 IL-10（目标 1）以及疟疾特异性 T 细胞对整个寄生虫抗原的反应（目标 2）。化学预防。在第三个目标中，他将对 IL-10 产生与疟疾特异性 T 细胞反应之间的关联进行组内分析，以及这些反应是否随后与未来疟疾发病率的降低相关。通过有针对性的指导培训和课程，候选人将培养转化免疫学、临床研究设计以及在资源有限的环境中进行疟疾转化研究方面的高级技能。完成时获得该奖项后，Jagannathan 博士将能够开发 R01 应用程序，以进一步定义疟疾保护性免疫的相关性和机制。