AUTOLOGOUS GRAFT VS HOST DISEASE

自体移植物与宿主疾病

• 批准号: 6101665
• 负责人: Allan D Hess
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6101665
• 关键词: T cell receptor; acute leukemia; adolescence (12-20); adult human (21+); antigen presenting cell; artificial immunosuppression; autoantigens; autologous transplantation; blood /lymphatic neoplasm; bone marrow transplantation; breast neoplasms; busulfan; cell mediated cytotoxicity; child (0-11); clinical research; clinical trials; cyclophosphamide; female reproductive system neoplasm; flow cytometry; graft versus host disease; histology; human subject; human therapy evaluation; in situ hybridization; interferon gamma; interleukin 2; laboratory rat; leukemia; lymphoma; molecular cloning; multiple myeloma; neoplasm /cancer immunotherapy; ovary neoplasms; protein sequence; tissue /cell culture

Autologous bone marrow transplantation (BMT) is effective therapy for patients with high-risk lymphomas and acute leukemias. Autologous BMT has also shown promising preliminary results in some drug-responsive solid tumors like breast and ovarian cancer. Tumor recurrence is the major cause of autologous BMT failure. Modification of cytotoxic preparative regimens has not made impact on occurrence of tumor relapse after autologous BMT. Moreover, currently used cytotoxic regimens for BMT are at or near non- hematologic dose-limiting toxicity hindering a further increase in the intensity of these preparative regimens. Innovative approaches for improving the antitumor activity of autologous BMT are therefore needed. A syndrome similar to graft-versus-host disease (GVHD) can be induced with cyclosporine (CsA) in animal models of autologous GVHD. The animal studies demonstrate that this syndrome generates antitumor activity similar to that seen with allogeneic GVHD without significant post-transplant mortality. This syndrome is mediated by autoreactive T-lymphocytes directed against Ia antigens. Both animal models and clinical data demonstrate that it should be possible to amplify the antitumor effect associated with autologous GVHD by modulating the effector and/or the target cells. The interferons, that upregulate Ia antigen expression on tumor cells, and low-dose IL-2 enhance the antitumor effect of autologous GVHD, without increasing toxicity. The overall aim of this aim of this proposal is to continue studies on the antitumor effect of autologous GVHD in preclinical models and clinically. Specifically, animal models will be used to further investigate the mechanisms responsible for the antitumor effect of autologous GVHD and to examine approaches for enhancing the antitumor effect particularly by enhancing tumor cell recognition. Clinical studies of CsA-induced autologous GVHD will be based on the principles developed from the preclinical studies. Laboratory studies monitoring the immunomodulatory effects of autologous GVHD will guide the clinical trials, particularly as to the best means to enhance the antitumor efficacy of autologous GVHD.

自体骨髓移植（BMT）是有效的治疗 适用于高危淋巴瘤和急性白血病的患者。 自体BMT还显示了一些有希望的初步结果 药物反应性实体瘤，例如乳腺癌和卵巢癌。瘤 复发是自体BMT失败的主要原因。 细胞毒性制备方案的修改尚未产生影响 自体BMT后肿瘤复发发生时。而且， 目前使用的BMT的细胞毒性方案在非 - 血液学剂量限制毒性进一步增加 这些制备方案的强度。创新的方法 因此，用于改善自体BMT的抗肿瘤活性 需要。 类似于移植物抗宿主病（GVHD）的综合征可以 在自体的动物模型中用环孢星（CSA）诱导 GVHD。动物研究表明该综合征产生 抗肿瘤活性类似于没有同种异体GVHD的抗肿瘤活性 重大移植后死亡率。该综合征是由 针对IA抗原的自动反应性T淋巴细胞。两种动物 模型和临床数据表明，应该有可能 扩增与自体GVHD相关的抗肿瘤效应 调节效应子和/或目标细胞。干扰素， 上调肿瘤细胞上的IA抗原表达和低剂量 IL-2增强了自体GVHD的抗肿瘤效应 毒性增加。该提议的总体目的 是继续研究自体GVHD的抗肿瘤作用 在临床前和临床上。具体而言，动物模型 将用于进一步调查负责的机制 自体GVHD的抗肿瘤作用并检查方法 以增强抗肿瘤效果，特别是通过增强肿瘤 细胞识别。 CSA诱导的自体GVHD的临床研究 将基于临床前制定的原理 研究。监测免疫调节作用的实验室研究 自体GVHD将指导临床试验，特别是 最佳手段增强自体的抗肿瘤功效 GVHD。