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Biology of SV40-Specific Transplantation Antigen

SV40 特异性移植抗原的生物学

基本信息

批准号：
7237983
负责人：
Todd D Schell
金额：
$ 63.11万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-06-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7237983
关键词：
Biological Factors Biology C57BL/6 Mouse CD8B1 gene Cells Choroid Plexus Neoplasms Cytotoxic T-Lymphocytes DNA DNA Viruses Development Epitopes Grant Histocompatibility Antigens Immune Immune response Immunization Immunodominant Epitopes Immunologic Surveillance In Vitro Light Lymphocyte Maintenance Malignant Neoplasms Mature T-Lymphocyte Mediating Modeling Mus Mutation Nature Neoplasm Metastasis Neoplasms Normal Cell Oncogenes Oncogenic Viruses Pancreas Peripheral Phenotype Play Positioning Attribute Role SV40 T Antigens Simian virus 40 Site System T memory cell T-Cell Receptor T-Lymphocyte Tissues Transgenes Transgenic Mice Transgenic Organisms Vaccinia virus Variant Viral Tumor Antigens base cell mediated immune response cell transformation design in vivo insight osteosarcoma promoter reconstitution response sialosyl-T antigen tumor tumor growth tumor progression tumorigenic vaccinia virus vector

项目摘要

SV40 is a small DNA containing tumor virus that encodes a 94 kD oncogene, tumor or T antigen, which converts normal cells to tumorigenic phenotype both in vitro and in vivo. T antigen-induced tumor progression is heavily influenced by the T cell-mediated immune response to T antigen. The T antigen induces CD8 ? T lymphocyte responses to four H2 b epitopes in B6 mice in a hierarchical manner (IV>I>II/III>V). In fact, CD8+ T cells specific for epitope V are not detected unless the immunodominant epitopes I, II/III and IV have been inactivated. Thus, the T antigen system provides an opportunity to study the role of CD8+ T cells specific for multiple epitopes in the control of spontaneous T antigen-induced tumors and to identify biological factors which contribute to immunodominance. In the previous grant period we characterized the T antigen-specific CD8+ T cell response in several T antigen transgenic mouse lines. Using a model of central T cell tolerance we found that adoptively transferred donor cells could be ensitized against the endogenous T antigehl leading to the induction of epitope IV-specific CD8 ? T cells that migrated to the tumor site and were associated with control of tumor progression. Additionally, we established a model of peripheral T cell tolerance in which T antigen epitope-specific CD8+ T cells were differentially tolerized before or in association with spontaneous tumor progression. Thus, the overall objectives of this project are to identify those aspects of the CD8 ? T cell immune response to T antigen which are critical for the control of spontaneous tumor progression in T antigen transgenic mice and to understand the basis for the immunorecessive nature of epitope V in the immune response to T antigen. The following four specific aims are _Dro0osed: 1. Requirements for effective CD8 ? T cell-mediated control of advanced choroid plexus tumors in T antigen transgenic mice with central CD8 ? T cell tolerance. 2. Counteracting peripheral tolerance for the control of tumor progression in T antigen transgenic mice. 3. CD8 ? T cell control of tumor metastasis in T antigen transgenic mice. 4. Immunodomination of epitope V CD8 ? T cell responses by dominant T antigen epitopes. We will utilize various models of T antigen transgenic mice and T antigen epitope-specific T cell receptor transgenic mice to determine the effect of various immunization approaches on the control of spontaneous tumor progression.

SV40是一种含有小DNA的肿瘤病毒，编码一个94kD的癌基因、肿瘤或T抗原，在体外和体内都能将正常细胞转化为肿瘤表型。T细胞对T抗原的免疫应答在很大程度上影响T抗原诱导的肿瘤进展。T抗原诱导CD8？B6小鼠T淋巴细胞对四个H2 b表位的分级反应(IV&gt；I&gt；II/III&gt；V)。事实上，除非免疫优势表位I、II/III和IV被灭活，否则不能检测到针对V表位的CD8+T细胞。因此，T抗原系统为研究针对多个表位的CD8+T细胞在自发性T抗原诱导的肿瘤控制中的作用以及识别有助于免疫优势的生物学因素提供了机会。在之前的资助期间，我们在几个T抗原转基因小鼠系中研究了T抗原特异性CD8+T细胞反应。利用中枢T细胞耐受模型，我们发现过继转移的供体细胞可以对内源性T抗原敏感，从而诱导表位IV特异性CD8？迁移到肿瘤部位并与肿瘤进展控制相关的T细胞。此外，我们建立了一个外周T细胞耐受模型，在该模型中，T抗原表位特异性CD8+T细胞在自发肿瘤进展之前或与之相关时具有不同的耐受性。因此，这个项目的总体目标是确定CD8的哪些方面？T细胞对T抗原的免疫应答对于控制T抗原转基因小鼠的自发肿瘤进展以及了解T抗原免疫应答中表位V的免疫隐性性质的基础至关重要。以下四个具体目标被放弃：1.有效的CD8的要求？T细胞介导的中枢性CD8 T抗原转基因小鼠对晚期脉络丛肿瘤的控制T细胞耐受性。2.抑制T抗原转基因小鼠外周耐受以控制肿瘤进展。3.CD8？T细胞对T抗原转基因小鼠肿瘤转移的调控4.表位V CD8的免疫优势？T细胞通过优势T抗原表位进行反应。我们将利用T抗原转基因小鼠和T抗原特异性T细胞受体转基因小鼠的各种模型来确定不同的免疫方法在控制自发肿瘤进展中的作用。