AUTOLOGOUS GRAFT VS HOST DISEASE

自体移植物与宿主疾病

• 批准号: 6592137
• 负责人: Allan D Hess
• 金额: $ 22.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-09 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6592137
• 关键词: MHC class II antigen; T cell receptor; T lymphocyte; artificial immunosuppression; autologous transplantation; bone marrow transplantation; breast neoplasms; chimeric proteins; chronic myelogenous leukemia; clinical research; cyclophosphamide; graft versus host disease; histology; human subject; human therapy evaluation; laboratory rat; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; tumor antigens

DESCRIPTION: (provided by Applicant) Cyclosporine (CsA), an effective immunosuppressive drug, paradoxically disrupts the mechanisms governing self tolerance during reconstitution of the immune system. Administration of CsA after autologous bone marrow transplantation (ABMT) in rodent models and in man elicits a T-cell dependent autoimmune syndrome with pathology identical to graft-vs-host disease (GVHD) that occurs after BMT. Ongoing studies analyzing the autoreactive lymphocytes in this syndrome termed auto GVHD, provide a unique insight into experimental strategies that augment recognition of tumor associated (TA) antigens. The autoreactive T-cells recognize MHC class II molecules in association with a peptide from the invariant chain, termed CLIP. A specific interaction between the N-terminal region of CLIP and the V-beta segment of the T-cell receptor (TCR) not only strengthens the TCR-MHC class II - CLIP complex, but also apparently overrides the requirements for classical cell surface restricting elements (i.e. CD4, CD8). Preliminary studies reveal that immunization with chimeric peptide constructs of the N-terminal fragment of CLIP and peptides from TA antigens elicit protective antitumor immunity. The central objective of this proposal, to augment specific antitumor immunity after ABMT, is based on the hypothesis that the N-terminal flanking region of CLIP augments recognition of peptides from TA antigens. The development of vaccine strategies in the setting of auto GVHD is particularly attractive since CsA alters the peripheral T-cell repertoire by allowing the emergence of autoreactive cells from the thymus that can recognize "self" TA antigens. The efficacy of peptide/chimeric peptide vaccines to augment antitumor immunity in auto GVHD will be assessed utilizing a rat tumor model that expresses the Her- 2/neu oncogene. In addition, the efficacy of anti-TA antigen reactive lymphocytes activated with the chimeric peptides will be assessed for their ability to augment antitumor immunity in vivo. Clinical trials will be developed based on the results from the animal model.

描述：（由申请人提供）环孢菌素（CSA），有效 免疫抑制药物，自相矛盾地破坏了自我的机制 免疫系统重建期间的耐受性。 CSA管理 自体骨髓移植（ABMT）之后，在啮齿动物模型和 人会引起T细胞依赖性自身免疫性综合征，病理学与 BMT之后发生的移植-VS宿主病（GVHD）。 正在进行的研究分析 该综合征称为自动GVHD的自动反应性淋巴细胞，提供 对实验策略的独特见解，增强对肿瘤的认识 相关（TA）抗原。 自动反应性T细胞识别MHC II类 与不变链的肽相关的分子称为夹子。 夹子的N末端区域与V-beta之间的特定相互作用 T细胞受体（TCR）的片段不仅增强了TCR-MHC II类 - 夹子复合物，但显然也覆盖了经典的要求 细胞表面限制元素（即CD4，CD8）。 初步研究表明 用N末端片段的嵌合肽构建体免疫 TA抗原的夹子和肽的含量会引起保护性抗肿瘤免疫。 该提案的核心目标，以增强特定的抗肿瘤免疫力 ABMT之后，基于以下假设。 夹子增强了对TA抗原的肽的识别。 发展的发展 在自动GVHD的情况下，疫苗策略特别有吸引力 由于CSA通过允许出现来改变周围的T细胞曲目 来自胸腺的自动反应性细胞，可以识别“自我”抗原。 这 肽/嵌合肽疫苗的功效增强抗肿瘤免疫力 使用大鼠肿瘤模型来评估自动GVHD 2/neu癌基因。 另外，抗TA抗原反应性的功效 将评估用嵌合肽激活的淋巴细胞 在体内增强抗肿瘤免疫力的能力。 临床试验将是 根据动物模型的结果开发。