Tracking Immune Activation by Stress Proteins In Vivo

体内应激蛋白追踪免疫激活

基本信息

批准号：
7183492
负责人：
CHRISTOPHER A PENNELL
金额：
$ 25.25万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7183492
关键词：
Accounting Address Adjuvant Adjuvanticity Adoptive Transfer Affect Amino Acids Animal Model Antigens Binding Biology CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cell Surface Receptors Cell Survival Cells Chickens Chimeric Proteins Data Dendritic Cells Dopachrome isomerase Employee Strikes Event Flow Cytometry Fluorochrome Frequencies Generations Goals Heat shock proteins Hour Immune Immune response Immune system Immunization Kinetics Life Link Longevity Maintenance Measures Mediating Memory Monoclonal Antibodies Mus Mycobacterium tuberculosis Numbers Peptides Phenotype Production Proliferating Proteins Reporting Research Personnel Signal Transduction Stress-Induced Protein System T memory cell T-Cell Activation T-Lymphocyte Testing Time Transgenic Organisms Tumor Immunity Vaccines Viral base cancer therapy cell type cytokine day density in vivo insight lymph nodes melanocyte novel programs receptor research study response stress protein uptake vaccine development

项目摘要

DESCRIPTION (provided by applicant): Vaccines containing peptides linked to stress proteins are the most potent known T cell immunogens. However, the precise mechanisms by which they activate immune cells remain unclear. To address this, we will track activated dendritic cells (DCs) and CD8+ T cells in mice immunized with antigens fused to the stress protein hsp70, and determine which cytokines and cell surface receptors are required for their responses. Our preliminary studies reveal hspTO fusion vaccines elicit much more potent and durable specific CD8+ T cell responses than antigen alone or with other adjuvants. Our underlying hypothesis is that antigen/hsp70 fusions are potent vaccines because they stimulate DCs to provide an optimal microenvironment for CD8+ T cell activation. This microenvironment is defined by high antigen density and strong costimulation. To test this, we will track in vivo DC and CD8+ T cell responses in draining lymph nodes, and the resultant effector and memory CD8+ T lymphocytes in the periphery. Novel aspects of our proposal include: 1) quantifying the amount of antigen presented by activated DCs, 2) the effect hsp70 fusion proteins have on DC lifespan, 3) determining which of the several reported hsp70-receptors are necessary or sufficient for delivering activation signals to DCs in vivo, and 4) determining the costimulatory and cytokines required for the profound effect our vaccine has CD8+ T cell memory. The results of these experiments will allow us to manipulate stress protein-induced responses rationally with the ultimate goal of maximizing their use for cancer therapy.

描述（由申请人提供）：含有与应激蛋白连接的肽的疫苗是已知最有效的 T 细胞免疫原。然而，它们激活免疫细胞的确切机制仍不清楚。为了解决这个问题，我们将追踪用与应激蛋白 hsp70 融合的抗原免疫的小鼠中激活的树突状细胞 (DC) 和 CD8+ T 细胞，并确定它们的反应需要哪些细胞因子和细胞表面受体。我们的初步研究表明，hspTO 融合疫苗比单独使用抗原或与其他佐剂一起引发更有效和更持久的特异性 CD8+ T 细胞应答。我们的基本假设是抗原/hsp70 融合是有效的疫苗，因为它们刺激 DC 为 CD8+ T 细胞激活提供最佳的微环境。这种微环境由高抗原密度和强共刺激定义。为了测试这一点，我们将追踪引流淋巴结中的体内 DC 和 CD8+ T 细胞反应，以及外周产生的效应和记忆 CD8+ T 淋巴细胞。我们提案的新颖之处包括：1) 量化活化 DC 呈递的抗原量，2) hsp70 融合蛋白对 DC 寿命的影响，3) 确定所报告的几种 hsp70 受体中的哪些对于传递激活信号是必要或充分的4) 确定我们的疫苗具有 CD8+ T 细胞记忆的深远影响所需的共刺激和细胞因子。这些实验的结果将使我们能够合理地操纵应激蛋白诱导的反应，最终目标是最大限度地利用它们在癌症治疗中的应用。