Molecular mechanisms for TNF-mediated inhibition of B lymphocyte function

TNF介导的B淋巴细胞功能抑制的分子机制

• 批准号: 8243804
• 负责人: BONNIE B. BLOMBERG
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243804
• 关键词: Address; Affect; Age; Aging; Antibodies; Antibody Formation; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Brain; Cell Culture Techniques; Cell physiology; Cells; Chronic; Communicable Diseases; Confocal Microscopy; Data; Defect; Development; Disease; Elderly; Feedback; Future; Goals; Heart; Hemagglutination; Human; Immune System Diseases; Immune response; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunoglobulins; Impairment; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-4; Lead; Lymphocyte Function; Malignant Neoplasms; Measures; Mediating; Memory; Memory B-Lymphocyte; Messenger RNA; Molecular; Mus; Outcome Measure; Pathogenesis; Plasma; Proteins; Quality of life; Regulation; Serum; Source; Staining method; Stains; Stimulus; T-Lymphocyte; TIS11 protein; TNF gene; TNFRSF5 gene; Testing; Tumor Necrosis Factor-alpha; Vaccination; Vaccine Antigen; Vaccines; Work; activation-induced cytidine deaminase; age related; aged; anti-influenza; autocrine; base; cell type; cytokine; disabling disease; exhaust; human TNF protein; immune function; impaired capacity; improved; in vivo; influenza virus vaccine; innovation; mRNA Expression; mRNA Stability; macrophage; monocyte; novel; peripheral blood; prevent; research study; response; restoration; Address; Affect; Age; Aging; Antibodies; Antibody Formation; Antigens; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Biological Assay; Biological Markers; Brain; Cell Culture Techniques; Cell physiology; Cells; Chronic; Communicable Diseases; Confocal Microscopy; Data; Defect; Development; Disease; Elderly; Feedback; Future; Goals; Heart; Hemagglutination; Human; Immune System Diseases; Immune response; Immunoglobulin Class Switching; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunoglobulins; Impairment; In Vitro; Incubated; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-4; Lead; Lymphocyte Function; Malignant Neoplasms; Measures; Mediating; Memory; Memory B-Lymphocyte; Messenger RNA; Molecular; Mus; Outcome Measure; Pathogenesis; Plasma; Proteins; Quality of life; Regulation; Serum; Source; Staining method; Stains; Stimulus; T-Lymphocyte; TIS11 protein; TNF gene; TNFRSF5 gene; Testing; Tumor Necrosis Factor-alpha; Vaccination; Vaccine Antigen; Vaccines; Work; activation-induced cytidine deaminase; age related; aged; anti-influenza; autocrine; base; cell type; cytokine; disabling disease; exhaust; human TNF protein; immune function; impaired capacity; improved; in vivo; influenza virus vaccine; innovation; mRNA Expression; mRNA Stability; macrophage; monocyte; novel; peripheral blood; prevent; research study; response; restoration

DESCRIPTION (provided by applicant): Aging is associated with a decline in the ability of the individual to mount protective immune responses. Understanding the molecular mechanisms of the age-related impairment in immune functions will help to prevent infectious diseases and improve the biological quality of life in the elderly. Aging is characterized by increased plasma levels of pro-inflammatory cytokines such as TNF-alpha, and these can have deleterious effects as they are implicated in the pathogenesis of several disabling diseases of the elderly. We hypothesize that this pro-inflammatory status of the elderly, called inflammaging, impairs the capacity of the individual to make protective antibodies and to respond to vaccination. Specifically, our preliminary data indicate that the increased inflammatory response typical of old age is also contributed by B lymphocytes and this negatively impacts their function , including the ability to undergo class switch recombination (CSR) of immunoglobulin (Ig), critical for optimal effector function of antibodies specific for exogenous antigens. In this R21 application we will characterize novel molecular mechanisms leading to reduced B cell responses in the elderly which in the future should be able to be used as new targets for their improvement. We will evaluate whether B cells ex vivo isolated from elderly individuals make more TNF-alpha than those from younger ones, determine which B cell subset makes TNF-alpha, and how much compared to other cell types known to be primary sources of this cytokine. Particular questions addressed are whether the intrinsic defect of B cells from elderly individuals in Ig class switch is due to the initial ability of the B cell to make TNF-alpha. This will also be correlated with the in vivo anti-influenza vaccine response in these subjects. We will characterize the mechanisms by which TNF-alpha impairs the ability of B cells to undergo CSR by pre-incubating B cell cultures with TNF-alpha and evaluate if the in vitro Ig class switch can be "rescued" with an anti-TNF-alpha antibody added to cultured B cells. Outcome measures will be molecular biomarkers we have previously discovered to predict optimal B lymphocyte responses. The experiments proposed in this R21 application offer an innovative approach to characterize further mechanisms which decrease B cell responses in elderly individuals. These studies should have immediate impact on crucial development of effective vaccines to protect elderly individuals from diseases typical of old age. PUBLIC HEALTH RELEVANCE: The studies proposed here investigate novel molecular mechanisms for decreased human B lymphocyte and antibody responses, important for optimal response to vaccines, infectious diseases, and cancer. These mechanisms may also help to explain the overall increase seen in inflammation in the elderly, which contributes to disorders of the immune system, heart, and brain.

描述（由申请人提供）：衰老与个体安装保护性免疫反应的能力的下降有关。了解免疫功能中与年龄相关的损伤的分子机制将有助于预防传染病并改善老年人的生物生活质量。 衰老的特征是血浆促炎性细胞因子（例如TNF-α）的血浆水平升高，并且这些因素可能具有有害作用，因为它们与几种致残疾病的发病机理有关。我们假设，称为炎症的老年人的促炎状态会损害个人制造保护性抗体并对疫苗接种反应的能力。具体而言，我们的初步数据表明，B淋巴细胞的典型炎症反应增加也由B淋巴细胞促成，这对它们的功能产生了负面影响，包括经历免疫球蛋白（IG）的类别转换重组（CSR）的能力，对抗体的最佳抗体功能的特异性抗皮质功能至关重要。 在此R21应用中，我们将表征新的分子机制，从而导致老年人的B细胞反应降低，这将来应该能够用作其改进的新目标。我们将评估从老年人中分离出的B细胞是否比来自年轻α的B细胞产生更多的TNF-α，确定哪种B细胞子群使TNF-Alpha产生TNF-Alpha，以及与已知是该细胞因子主要来源的其他细胞类型相比，多少。解决的特定问题是，IG类开关中老年人的B细胞的固有缺陷是否是由于B细胞制造TNF-Alpha的初始能力。 这也将与这些受试者中体内抗炎性疫苗反应相关。 我们将表征TNF-Alpha损害B细胞通过预孵育B细胞培养TNF-Alpha的能力的机制，并评估是否可以用抗TNF-Alpha抗体添加到培养的B细胞中“营救体外IG类开关”。 结果度量将是我们以前发现的分子生物标志物，以预测最佳的B淋巴细胞反应。 在此R21应用中提出的实验提供了一种创新的方法，可以表征进一步的机制，从而降低了老年人的B细胞反应。这些研究应立即对有效疫苗的关键发展产生影响，以保护老年人免受典型的老年疾病。 公共卫生相关性：此处提出的研究研究了人类B淋巴细胞和抗体反应减少的新型分子机制，对于对疫苗，传染病和癌症的最佳反应至关重要。这些机制也可能有助于解释老年人炎症的总体增加，这导致了免疫系统，心脏和大脑的疾病。