Molecular immunologic role of cytokines in the development of malarial immunity

细胞因子在疟疾免疫发展中的分子免疫作用

基本信息

批准号：
7291163
负责人：
John Michael Ongecha
金额：
$ 5.08万
依托单位：
KENYA MEDICAL RESEARCH INSTITUTE (KEMRI)
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7291163
关键词：
Acute Affect African Age Age-Years Anemia Animal Model Anti-Inflammatory Agents Anti-inflammatory Antibodies Antibody Formation Antibody-Producing Cells Antigens Area B-Lymphocytes Biological Assay Blood CD4 Positive T Lymphocytes Cell surface Cells Child Childhood Chronic Clinical Condition Development Disease Disease Outcome Enrollment Enzyme-Linked Immunosorbent Assay Erythrocyte Membrane Erythrocytes Erythrophagocytosis Erythropoiesis Falciparum Malaria Functional disorder Funding Gender Generations Genetic Goals HLA-DR Antigens Hemolysis Hospitals Immune response Immunity Immunoglobulin G Immunoglobulin M Immunologics In Vitro Individual Infant Inflammatory Interferon Type II Interferons Interleukin-10 Interleukin-12 Interleukin-17 Interleukin-18 Interleukins Investigation Kenya Life Malaria Malaria Vaccines Measurement Measures Membrane Proteins Memory Merozoite Surface Protein 1 Modeling Molecular Mus Numbers Outcome Parasites Pathogenesis Pathway interactions Plasma Population Principal Investigator Production Property Recovery Relative (related person)Reporting Research Infrastructure Research Personnel Role SELL gene Sampling Schedule Severity of illness Signal Pathway Specimen Staging Standards of Weights and Measures Surface T-Lymphocyte T-Lymphocyte Subsets Testing United States National Institutes of Health Vaccines Visit base conditioning cytokine day density enzyme linked immunospot assay follow-up interleukin-23 macrophage memory CD4 T lymphocyte monocyte novel programs receptor repository research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): Severe malarial anemia (SMA) is the primary clinical manifestation of Plasmodium falciparum malaria in African children in holoendemic areas of malaria transmission. Dysregulation in pro- and anti-inflammatory cytokine production is associated with enhanced pathogenesis of SMA in infants and young children. Interleukin (IL)-12 is a pro-inflammatory cytokine associated with protection against childhood SMA. IL-23 is a recently discovered pro-inflammatory cytokine that shares a common p40 subunit with IL-12. Although not investigated in the context of SMA, IL-23 is associated with the pathogenesis of anemia in chronic inflammatory diseases. Moreover, both IL-12 and IL-23 initiate innate immune responses that are down- regulated by IL-10. Both IL-12 and IL-23 have also been reported to be important in the induction of antibody production. Protective innate immune responses occur through IL-18 synergizing with IL-12 to induce interferon (IFN)-gamma production from naive CD4+ T cells, while IL-23 promotes IL-17 production from activated memory CD4+ T cells. The primary goal of this proposal is to investigate the role of the IL-12 and IL-23 cytokine pathways during childhood malarial anemia. This will be accomplished by; 1) determining the association between IL-12 and IL-23 signaling pathways with malarial anemia disease severity; 2) determining the association between IL-12 and IL-23-induced CD4+ T cell responses and malarial anemia disease outcomes; and 3) determining the effect of IL-12 and IL-23 on the in vitro induction of IFN-gamma and IL-17, respectively, and the generation of antibody responses to malaria antigen stimulation. Successful completion of these experimental objectives will provide novel and important information about the role of the IL-12 and IL-23 cytokine pathways in regulating protective clinical immunity in young children naturally exposed to holoendemic P. falciparum malaria transmission.

描述（申请人提供）：严重疟疾贫血（SMA）是疟疾传播流行地区非洲儿童恶性疟原虫疟疾的主要临床表现。促炎和抗炎细胞因子产生的失调与婴儿和幼儿 SMA 的发病机制增强有关。白细胞介素 (IL)-12 是一种促炎细胞因子，与预防儿童 SMA 相关。 IL-23 是最近发现的一种促炎细胞因子，与 IL-12 具有共同的 p40 亚基。尽管没有在 SMA 背景下进行研究，但 IL-23 与慢性炎症性疾病贫血的发病机制有关。此外，IL-12 和 IL-23 都会启动先天免疫反应，而 IL-10 会下调该反应。据报道，IL-12 和 IL-23 在诱导抗体产生中也很重要。保护性先天免疫反应通过 IL-18 与 IL-12 协同作用来诱导初始 CD4+ T 细胞产生干扰素 (IFN)-γ，而 IL-23 则促进激活的记忆 CD4+ T 细胞产生 IL-17。该提案的主要目标是研究 IL-12 和 IL-23 细胞因子途径在儿童疟疾贫血期间的作用。这将通过以下方式完成： 1) 确定IL-12和IL-23信号通路与疟疾贫血疾病严重程度之间的关联； 2) 确定 IL-12 和 IL-23 诱导的 CD4+ T 细胞反应与疟疾贫血疾病结果之间的关联； 3)确定IL-12和IL-23分别对体外诱导IFN-γ和IL-17以及对疟疾抗原刺激产生抗体反应的影响。这些实验目标的成功完成将提供有关 IL-12 和 IL-23 细胞因子途径在调节自然暴露于恶性疟原虫恶性疟传播的幼儿的保护性临床免疫中的作用的新颖且重要的信息。