AUTOLOGOUS GRAFT VS HOST DISEASE

描述：(申请人提供)有效的环孢素(CsA) 免疫抑制药物，矛盾地扰乱了自我控制的机制 免疫系统重建过程中的耐受性。CsA的管理 自体骨髓移植(ABMT)后在啮齿动物模型和 一名男子引发T细胞依赖性自身免疫综合征，其病理与 骨髓移植后发生的移植物抗宿主病(GVHD)。正在进行的研究分析 在这种称为自体移植物抗宿主病的综合征中，自身反应性淋巴细胞提供了一种 对增强肿瘤识别的实验策略的独特见解 相关(TA)抗原。自身反应性T细胞识别MHC II类 与来自不变链的多肽结合的分子，称为片段。 CLIP的N-末端区域与V-β的特异性相互作用 T细胞受体(TCR)的片段不仅增强TCR-MHC II类 -剪辑复杂，但也明显超越了对古典音乐的要求 细胞表面限制因子(即CD4、CD8)。初步研究显示 用嵌合肽免疫构建了N-末端片段 TA抗原的Clip和多肽可诱导保护性抗肿瘤免疫。 这项提议的中心目标是增强特异性抗肿瘤免疫 在ABMT之后，是基于假设的N末端侧翼区 CLIP增强了对TA抗原中的多肽的识别。的发展。 在汽车GVHD的背景下的疫苗策略特别吸引人 由于CsA改变了外周T细胞谱系，允许出现 来自胸腺的能识别“自身”TA抗原的自身反应细胞。这个 多肽/嵌合多肽疫苗增强小鼠抗肿瘤免疫效果的研究 Auto GVHD将利用表达HER-1的大鼠肿瘤模型进行评估。 2/neu癌基因。此外，抗TA抗原反应的疗效 用嵌合肽激活的淋巴细胞将被评估其 体内增强抗肿瘤免疫的能力。临床试验将是 根据动物模型的结果开发的。

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.