CD138 Regulates Competition of Antibody Secreting Cells for Survival

CD138 调节抗体分泌细胞的生存竞争

基本信息

批准号：
9906270
负责人：
David R Fooksman
金额：
$ 50.18万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906270
关键词：
Address Adjuvant Antibodies Antibody Affinity Antibody Formation Antibody Response Antibody titer measurement Antigens Apoptosis Attenuated Autoimmune Diseases Autoimmune Process B-Lymphocytes Binding Blood Bone Marrow Cell Maturation Cell Survival Cells Chronic Cytokine Signaling Disease Disease Progression Effector Cell Engraftment Genetic Transcription Genus Mentha Grant Growth Hematopoietic Heparitin Sulfate Human IL6 gene Immune Immune response Immunity Immunization Immunoglobulin-Secreting Cells Infection Inflammation Interleukin 6 Receptor Interleukin-6 Lupus Lymphoid Tissue Malignant Neoplasms Mediating Modeling Multiple Myeloma Mus Pathogenicity Pathologic Patients Phenotype Plasmablast Population Production Prophylactic treatment Proteins Publishing Receptor Signaling Rheumatoid Arthritis Role Signal Pathway Stress Surface TLR4 gene Testing Time Vaccination Vaccines Virus adoptive B cell transfer autoreactivity base cytokine human model immune function improved in vivo migration mouse model prevent transcription factor vaccine efficacy vaccine response

项目摘要

Long-lived antibody secreting cells (LLASCs) are critical immune effector cells constitutively secreting high affinity antibody providing prophylaxis against infections. In contrast to live attenuated viruses which can provide lifelong immunity, protein-based vaccines are known to poorly induce LLASCs, often requiring multiple boosting to generate sufficient antibody titer. The factors that control LLASC production are poorly understood, but are critically important for all humoral-based vaccines. Survival of LLASCs is chiefly mediated by soluble cytokines, such as APRIL in the BM, and IL-6 in secondary lymphoid tissues. After immunization, antibody secreting cells (ASCs) express variable levels of CD138, and its function was unclear, since it can bind 100+ proteins, and CD138-/- have no overt phenotype. However, we have recently published a study that finally details a direct role for CD138 for potent antibody responses, by controlling ASC maturation and survival after immunization. LLASCs express the highest level of CD138 among all cells, in comparison to newly minted ASCs, which express intermediate levels of CD138. We proposed that high expression of CD138 provides LLASCs with higher binding and accumulation of IL-6 and APRIL, which are limiting, leading to a competitive advantage over new ASCs for survival. In Aim 1, we will test this competition model in this grant, which can explain poor vaccine responses as well as how LLASCs are maintained over time and repeated immune responses. In Aim 2 we will explore ways to increase CD138 after vaccination to enhance ASC survival and long term immunity. In Aims 3 & 4, we will explore CD138 function in pathological conditions.

长寿命抗体分泌细胞（LLASC）是关键的免疫效应细胞组成型细胞分泌高亲和力抗体，可预防感染。与生活相反可以提供终身免疫力的减毒病毒，已知基于蛋白质的疫苗已知诱导LLASC的不良诱导，通常需要多重提升才能产生足够的抗体滴度。这控制LLASC生产的因素知之甚少，但对所有人都至关重要基于体液的疫苗。 Llascs的生存主要由可溶性细胞因子介导，例如 4月在BM中，在继发性淋巴组织中IL-6。免疫后，抗体分泌细胞（ASC）表达CD138的可变水平，其功能尚不清楚，因为它可以结合100+蛋白，CD138 - / - 没有明显的表型。但是，我们最近有发表了一项研究，最终详细介绍了CD138的直接作用，用于有效抗体反应，免疫后控制ASC成熟和存活。 Llascs表达最高水平与新铸造的ASC相比，所有细胞中CD138的of cd138 CD138的水平。我们提出，CD138的高表达为LLASC提供了较高的 IL-6和4月的约束和积累，这是限制的，导致竞争激烈优于新的ASC生存的优势。在AIM 1中，我们将在此测试该竞争模型格兰特（Grant）可以解释不良的疫苗反应以及如何维持LLASC 时间和反应反应。在AIM 2中，我们将探索在此后增加CD138的方法疫苗接种以增强ASC生存和长期免疫力。在目标3和4中，我们将探索 CD138在病理条件下的功能。