AUTOLOGOUS GRAFT VS HOST DISEASE

自体骨髓移植是一种有效的治疗方法 适用于高危淋巴瘤和急性白血病患者。 自体骨髓移植也显示出一些有希望的初步结果 对药物敏感的实体肿瘤，如乳腺癌和卵巢癌。肿瘤 复发是自体骨髓移植失败的主要原因。 细胞毒制剂方案的修改未产生影响 自体骨髓移植后肿瘤复发的研究。此外， 目前用于骨髓移植的细胞毒性方案是在或接近非 血液学剂量限制毒性阻碍进一步增加 这些准备养生法的强度。创新方法 因此，为了提高自体骨髓移植的抗肿瘤活性 需要的。类似移植物抗宿主病(GVHD)的综合征可以 环孢素(CsA)诱导自体移植瘤动物模型的建立 GVHD。动物研究表明，这种综合症会产生 抗肿瘤活性与无GVHD的同种异体GVHD相似 移植后的显著死亡率。这种综合症是由以下因素引起的 针对Ia抗原的自身反应性T淋巴细胞。两种动物都是 模型和临床数据表明，应该有可能 通过以下方法放大自体GVHD相关的抗肿瘤作用 调制效应器和/或靶细胞。干扰素， 上调肿瘤细胞上Ia抗原的表达，以及低剂量 IL-2增强自体GVHD的抗肿瘤作用 毒性越来越大。这项提案的总体目标是 是继续研究自体GVHD的抗肿瘤作用 在临床前模型和临床上。具体地说，动物模型 将被用于进一步调查负责 自体GVHD的抗肿瘤作用及研究途径 用于增强抗肿瘤作用，特别是通过增强肿瘤 细胞识别。环孢素A诱导自体移植物抗宿主病的临床研究 将基于从临床前发展而来的原则 学习。监测免疫调节作用的实验室研究 将指导临床试验，特别是作为 以最佳手段提高自体抗肿瘤效果 GVHD。

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.