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Negative regulation of Plasma cells by CD28 and B7 molecules

CD28 和 B7 分子对浆细胞的负调控

基本信息

批准号：
8513589
负责人：
JOSHY JACOB
金额：
$ 44.57万
依托单位：
EMORY UNIVERSITY
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：
2012-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513589
关键词：
Adopted Affect Antibodies Antibody Formation Antigens Asthma Autoimmune Diseases Autoimmunity Binding Bird Flu vaccine Bone Marrow CD28 gene Cell Surface Proteins Cell physiology Cells Cellular biology Data Disease Enhancing Antibodies Exhibits Experimental Autoimmune Encephalomyelitis Exposure to Feasibility Studies Health Human Immune response Immune system Immunity Infection Inflammation Influenza A Virus, H1N1 Subtype Influenza A Virus, H5N1 Subtype Interruption Invaded Knowledge Lead Life Ligands Longevity Mediating Mediator of activation protein Modeling Multiple Myeloma Mus Phenotype Plasma Cells Play Production Published Comment Reactive Plasma Cell Regulation Research Proposals Role Serological Serum Signal Transduction Smallpox Vaccine Source Stress Stromal Cells T-Cell Activation T-Lymphocyte Tail Testing Time Vaccines Vietnam Work base immunogenic in vivo influenzavirus knockout gene neutralizing antibody pathogen response seasonal influenza src-Family Kinases

项目摘要

DESCRIPTION (provided by applicant): Exposure to pathogens leads to the sustained production of serum antibodies for a life-time. For instance, humans immunized with smallpox vaccine exhibit stable levels of neutralizing antibodies in their serum for over 75 years. Antibodies are produced by plasma cells and these cells are critical effectors of the humoral immune system both in health (responses to pathogens) and in disease (autoimmunity) and hence, it is important to better understand how these cells are regulated and maintained. CD28 is a cell surface protein that is critical for the activation of na¿ve T cells. Interestingly, CD28is expressed also on plasma cells and multiple myeloma cells. Here we provide evidence that CD28 is expressed on both short-lived as well as long-lived plasma cells in the bone marrow. Very little is known about the function of CD28 on plasma cells. We also demonstrate that short- and long-lived plasma cells also express the ligands for CD28, B7.1 and B7.2. Based upon our compelling preliminary data, our central hypothesis is that CD28/B7 molecules are critical for the regulation of plasma cell function and modulation of this interaction using soluble CD28 or B7 molecules will enhance immune responses in vivo. We will test our central hypothesis by pursuing three specific aims. We will determine the extent to which CD28 (Aim 1) and B7. /B7.2 (Aim 2) affects plasma cell function and longevity and determine whether soluble CD28 or B7 can be used to enhance host immune responses to poorly-immunogenic H5N1 avian influenza vaccine (Aim 3). The proposed work is significant, because upon completion, we will have a better understanding of how CD28 and or B7 molecules modulate function and longevity of plasma cells. This could potentially be used to (a) enhance vaccine-induced Ab responses or (b) down modulate self-reactive plasma cells in autoimmune disorders.

描述（由申请方提供）：暴露于病原体导致终生持续产生血清抗体。例如，用天花疫苗免疫的人在其血清中表现出稳定水平的中和抗体超过75年。抗体由浆细胞产生，这些细胞是体液免疫系统在健康（对病原体的反应）和疾病（自身免疫）中的关键效应子，因此，更好地了解这些细胞是如何调节和维持的是很重要的。CD 28是一种细胞表面蛋白，对幼稚T细胞的活化至关重要。有趣的是，CD 28也在浆细胞和多发性骨髓瘤细胞上表达。在这里，我们提供的证据表明，CD 28表达的短寿命以及长寿命的骨髓浆细胞。关于CD 28在浆细胞上的功能知之甚少。我们还证明，短寿命和长寿命的浆细胞也表达CD 28，B7.1和B7.2的配体。基于我们令人信服的初步数据，我们的中心假设是，CD 28/B7分子对于调节浆细胞功能至关重要，并且使用可溶性CD 28或B7分子调节这种相互作用将增强体内免疫应答。我们将通过追求三个具体目标来检验我们的中心假设。我们将确定CD 28（Aim 1）和B7. /B7.2（目的2）影响浆细胞功能和寿命，并确定可溶性CD 28或B7是否可用于增强宿主对低免疫原性H5 N1禽流感疫苗的免疫应答（目的3）。这项工作意义重大，因为完成后，我们将更好地了解CD 28和/或B7分子如何调节浆细胞的功能和寿命。这可潜在地用于（a）增强疫苗诱导的Ab应答或（B）下调自身免疫性疾病中的自身反应性浆细胞。