Antigen Specific MOdulation of T Cell Responses

T 细胞反应的抗原特异性调节

• 批准号: 7046737
• 负责人: JONATHAN P SCHNECK
• 金额: $ 31.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7046737
• 关键词: MHC class I antigen; MHC class II antigen; T cell receptor; anergy; apoptosis; biological signal transduction; cell migration; cytolysis; cytotoxic T lymphocyte; diabetes mellitus; disease /disorder model; flow cytometry; genetically modified animals; hepatitis B; hepatitis B antigens; immunoglobulins; immunoregulation; laboratory mouse; leukocyte activation /transformation; tissue /cell culture; MHC class I antigen; MHC class II antigen; T cell receptor; anergy; apoptosis; biological signal transduction; cell migration; cytolysis; cytotoxic T lymphocyte; diabetes mellitus; disease /disorder model; flow cytometry; genetically modified animals; hepatitis B; hepatitis B antigens; immunoglobulins; immunoregulation; laboratory mouse; leukocyte activation /transformation; tissue /cell culture

DESCRIPTION (provided by applicant): Understanding the requirements for effective CTL activation and generation of memory CTL in vitro and in vivo is essential for the development of effective immunotherapy. During the previous funding period, we found that class I MHC-Ig fusion protein, MHC-Ig can be used to develop an artificial Antigen Presenting Cell, aAPC (see Appendix A) and stimulate antigen-specific CTL. In addition injection of MHC-Ig had immunomodulatory effects in vivo (see Appendix B). The goals of the current proposal are to further study the requirements for effective T cell stimulation by MHC complexes. Specifically we will study, the role of TCR affinity and costimulation on development of effector and memory CTL. Recent studies have shown that the "effective T cell recognition" is a complex phenotype which we hypothesize is based on increased TCR avidity. To analyze this question we will use a APC which can be optimized and used to stimulate antigen specific CTL and analyze their response using both functional CTL assays and a quantitative MHC-Ig binding assay that we previously developed. Experiments proposed will yield information on basic requirements for effective memory CTL development and also indicate how to best design systems such as aAPC for adoptive transfer of CTL. We will also analyze the efficacy of-in vivo immunization using soluble pepMHC-Ig molecules and peptide loaded MHC-Ig based aAPC. Our preliminary data show that pepMHC-Ig complexes can be used to immunize mice of interest, however this approach needs to be compared to more classic immunizations protocols for evaluation of efficacy. In addition while our preliminary data has focused on use of aAPC for in vitro expansion of CTL, aAPC could also have potential in vivo activity. In this Specific Aim we will compare immunization with soluble pep/MHC-Ig and MHC-Ig based a APC to a more classic immunization strategy. Finally, we will analyze the role of TCR avidity and induction of effective immune responses in the presence of endogenous antigen. Here we will analyze if the approaches developed in Specific Aims 1 and 2 are applicable to induction of T cells in a model system with a diverse TCR repertoire in the absence or presence of an endogenous antigen. Together these studies will further our insights into basic requirements for effective T cell stimulation and also highlight potential use of MHC-Ig in therapeutic settings.

描述（由申请人提供）：了解有效的CTL激活和内存CTL CTL的要求，对于开发有效的免疫疗法至关重要。在上一个资金期间，我们发现I类MHC-Ig融合蛋白，MHC-Ig可用于开发人工抗原呈现细胞，AAPC（请参阅附录A）并刺激抗原特异性CTL。另外，注射MHC-Ig在体内具有免疫调节作用（请参见附录B）。当前建议的目标是进一步研究MHC复合物有效T细胞刺激的要求。具体而言，我们将研究TCR亲和力以及共刺激对效应子和记忆CTL的发展的作用。最近的研究表明，“有效的T细胞识别”是我们假设的复杂表型，基于TCR的增加。为了分析这个问题，我们将使用APC，该APC可以进行优化和用于刺激抗原特异性CTL，并使用我们先前开发的功能性CTL分析和定量MHC-Ig结合测定法分析其响应。提出的实验将产生有关有效内存CTL开发基本要求的信息，并指示如何最好地设计系统（例如AAPC），用于采用CTL。我们还将使用可溶性PEPMHC-Ig分子和基于MHC-Ig的肽基于AAPC分析体内免疫的疗效。我们的初步数据表明，PEPMHC-Ig复合物可用于免疫感兴趣的小鼠，但是，需要将这种方法与更经典的免疫接种方案进行比较，以评估功效。此外，尽管我们的初步数据集中于使用AAPC进行CTL的体外扩张，但AAPC也可能具有体内活性。在这个具体目的中，我们将将免疫接种与可溶性PEP/MHC-Ig和MHC-Ig基于APC的APC与更经典的免疫策略进行比较。最后，我们将分析内源性抗原存在下TCR亲和力的作用和有效免疫反应的作用。在这里，我们将分析特定目标1和2中开发的方法是否适用于在没有内源性抗原的情况下具有多种TCR库的模型系统中T细胞的诱导。这些研究将共同​​进一步洞悉有效T细胞刺激的基本要求，并强调MHC-Ig在治疗环境中的潜在使用。