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）：这是加利福尼亚大学旧金山分校的传染病研究员Prasanna Jagannathan博士颁发的K23奖。该K23奖将为Jagannathan博士提供实现以下目标所需的支持：（1）研究抗疟疾化学预防对IL-10特异性反调节机制的发展和疟疾特异性T细胞反应的发展，并在高处的环境中确定这些反应与这些反应相关的儿童，以确定这些反应是否与众元相关联。为了实现这些目标，Jagannathan博士组建了一支由主要导师组成的指导团队，由一位主要导师玛格丽特·费尼（Margaret Feeney）博士组成，他是儿科转化免疫学专家，传染病的专家，三位同事：格兰特·多尔西（Grant Dorsey）博士，疟疾阶级的疟疾临床学家和PI，该样品是K23的疟疾临床试验。 Philip Rosenthal博士，疟疾寄生虫学和抗疟疾耐药性专家；以及艾滋病毒，结核病和疟疾临床研究的国际领导者黛安·哈夫利（Diane Havlir）博士。抗疟疾化学预防是一种新兴的方式，可防止居住在高度流行地区的儿童中疟疾的死亡和发病率，但人们担心它会延迟获得抗疟疾的获得。对小鼠和人类的最新研究提出了这种范式的挑战，并表明，使用抗疟药对血液阶段感染的选择性封锁可能会矛盾地增强消毒抗疟疾免疫的发展。 Jagannathan博士从正在进行的，NIH资助的抗疟疾化学预防的随机临床试验中利用样品，将检验一个中心假设，即化学预防抑制IL-10介导的反调控机制的产生，并允许开发多功能疟疾 - 疟疾---疟疾 - 症状CD4+ T细胞响应。具体而言，他将使用多参数流式细胞术（AIM 2）在随机分配的儿童中比较T细胞和其他免疫细胞群（AIM 1）和其他免疫细胞群体（AIM 1）和疟疾特异性T细胞对整个寄生虫抗原的反应（AIM 2），以接受有效的疟疾化学预防或不进行化学预防。在第三个目标中，他将对IL-10产生和疟疾特异性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疟疾未来发病率降低有关。通过专注的指导培训和课程计划，候选人将在资源有限的环境中发展转化免疫学，临床研究设计以及疟疾转化研究的高级技能。完成在该奖项中，Jagannathan博士将有能力开发R01应用程序，以进一步定义与疟疾的保护性免疫的相关和机制。