Immune Responses in Otitis Prone Children

易患中耳炎的儿童的免疫反应

• 批准号: 8823637
• 负责人: MICHAEL E PICHICHERO
• 金额: $ 64.28万
• 依托单位: ROCHESTER GENERAL HOSPITAL (NY)
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823637
• 关键词: Acute; Adherence; Adopted; Antibiotic Therapy; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; Automobile Driving; B-Lymphocytes; Bacteria; CD4 Positive T Lymphocytes; Cell physiology; Censuses; Child; Childhood; Clinical Research; Communicable Diseases; Cost Savings; Data; Defect; Development Plans; Diagnosis; Disease; Disease Progression; Drops; Epithelial; Epithelial Cells; Functional disorder; Funding; Future; Generations; Haemophilus Vaccines; Hearing; Helper-Inducer T-Lymphocyte; Immune; Immune response; Immunity; Immunologic Deficiency Syndromes; Immunologics; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Language Development; Lead; Mediator of activation protein; Methodology; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Natural Immunity; Neonatal; Nontypable Haemophilus influenza; Nose; Otitis; Otitis Media; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Population; Preparation; Proteins; Publications; Recurrence; Research; Resistance; Role; Serum; Shapes; Speech Development; Streptococcus pneumoniae; T memory cell; T-Lymphocyte; Toll-like receptors; Tympanostomy; Up-Regulation; Vaccines; Viral; Viral Tumor Antigens; Virus; Virus Diseases; adaptive immunity; aged; co-infection; cytokine; defined contribution; design; hearing impairment; immunogenicity; meetings; middle ear; pathogen; prospective; receptor; repository; respiratory; response; sample collection; time interval; trafficking; translational study; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Acute Otitis Media (AOM) is the most common infectious disease among children. During AOM, children typically have diminished hearing and this can lead to temporary delayed speech and language development and possibly permanent hearing loss. This project seeks support to continue our prospective, longitudinal clinical and translational studies of AOM (RO1 DC 08671) with a specific focus on defining the adaptive and innate immune response deficits among otitis prone (OP) children to infections caused by nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (Spn). To better understand NTHi and Spn pathogenesis and assist in vaccine development we plan to (1) identify specific adaptive immune deficits in OP children; (2) determine independent contributions of mucosal immunity in OP children; (3) understand the role of innate responses to co-infection of respiratory bacteria and viruses; and (4) define the role of differences in the nasopharyngeal (NP) inflammatory response in shaping the mucosal microenvironment to allow for NTHi/ Spn colonization and then infection. Therefore, we will investigate: 1. The mechanisms causing a diminished capacity to generate adaptive immune responses to NTHi and Spn following NP colonization and AOM in OP versus non-OP (NOP) children. We will define mechanisms causing poor T-cell function with respect to immune maturity and examine the capacity to generate memory T-cells, compare the generation and activity of NTHi/Spn specific B-cells, define key intrinsic differences of antigen-presenting cell function and evaluate mucosal immune responses. 2. The contributions of innate immunity that alters the NP microenvironment to favor NTHi and Spn colonization during concurrent viral infections to aid the pathogenesis of AOM. We will determine the level of NP and middle ear up-regulation of NTHi/Spn epithelial adherence receptors during antecedent respiratory viral infections; define the role of pro-inflammatory cytokine mediators induced by respiratory viral infections in modifying resistance to NTHi/Spn colonization; and characterize expression of toll like receptors (TLR) as mediators of innate and adaptive immune response clearance of NTHi/Spn colonization. During our current funding time interval, we have re-defined the OP child phenotype thereby providing new clarity and direction in the study of these children. Further understanding immune defects in OP children, will point the way to rational design of future candidate vaccines. Second, we will establish the key mediators of "controlled" inflammation in the NP during colonization that promote an effective immune response compared to pathological "uncontrolled" inflammation that allows disease progression. From that knowledge we can seek to modulate or silence those innate immune response pathways that facilitate disease progression while preserving the necessary innate responses that facilitate protective immunogenicity.

描述（由申请人提供）：急性中耳炎（AOM）是儿童中最常见的传染病。在AOM期间，儿童通常会减少听力，这可能导致暂时延迟的语音和语言发展以及可能永久性听力损失。该项目寻求支持，以继续我们对AOM的前瞻性，纵向临床和翻译研究（RO1 DC 08671），其特定重点是定义容易发生的适应性和先天免疫反应不足（OP）儿童（OP）儿童对由不可能的嗜血性嗜血杆菌（NTHI）和prepteptocccus pnecoccus pnee（NTHI）和pnecoccus pnee（NTHI）引起的感染引起的感染。为了更好地了解NTHI和SPN发病机理并有助于疫苗开发，我们计划（1）确定OP儿童的特定适应性免疫缺陷； （2）确定OP儿童中粘膜免疫的独立贡献； （3）了解对呼吸细菌和病毒共同感染的先天反应的作用； （4）定义差异在鼻咽（NP）炎症反应中的作用在塑造粘膜微环境中以允许NTHI/ SPN定植，然后再感染。因此，我们将研究：1。导致NP定植后对NTHI和SPN产生适应性免疫反应的能力降低的机制，而OP（NOP）儿童的AOM和AOM。我们将定义导致T细胞功能不良的免疫成熟度的机制，并检查产生记忆T细胞的能力，比较NTHI/SPN特异性B细胞的产生和活性，定义了抗原呈递细胞功能的关键内在差异并评估粘膜免疫反应。 2。在并发病毒感染期间，改变NP微环境的先天免疫力促进NP微环境有利于NTHI和SPN定植，以帮助AOM的发病机理。我们将确定在呼吸道病毒感染期间NTHI/SPN上皮依从性受体的NP和中耳上调的水平；定义呼吸道病毒感染诱导的促炎性细胞因子介质在改变对NTHI/SPN定殖的抗性中的作用；并将像受体（TLR）的表达表达为NTHI/SPN定植的先天和适应性免疫反应清除率的介体。在当前的资助时间间隔中，我们重新定义了OP子表型，从而在研究这些孩子的研究中提供了新的清晰度和方向。进一步了解OP儿童的免疫缺陷将为未来候选疫苗的合理设计指向道路。其次，我们将在定植期间建立NP中“受控”炎症的关键介质，与病理“不受控制”的炎症相比，促进了有效的免疫反应，从而允许疾病进展。从这些知识中，我们可以寻求调节或沉默那些促进疾病进展的先天免疫反应途径，同时保留促进保护性免疫原性的必要先天反应。