IRRADIATION AND MARROW TRANSPLANTATION

放射治疗和骨髓移植

• 批准号: 3169897
• 负责人: Rainer F. Storb
• 金额: $ 52.89万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-05-01 至 1996-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3169897
• 关键词: CD4 molecule; CD8 molecule; MHC class I antigen; MHC class II antigen; acetone; aminophosphonate; autologous transplantation; bone marrow transplantation; cell mediated cytotoxicity; cell mediated lymphocytolysis test; cellular immunity; cyclosporines; cytotoxicity; dogs; graft versus host disease; histocompatibility; histocompatibility antigens; histocompatibility typing; homologous transplantation; immunoconjugates; immunohematology; immunosuppressive; iodination; lymphocyte; major histocompatibility complex; methotrexate; monoclonal antibody; natural killer cells; radiation dosage; radiation immunosuppression; restriction fragment length polymorphism; splenectomy; succinates; whole body irradiation dosage; whole body irradiation effect

We propose to investigate 4 important questions in the areas of marrow transplantation and total body irradiation (TB1). Answers to these questions have relevance to human marrow transplantation for the treatment of patients with malignant and nonmalignant hematological diseases. We plan to carry out the studies in a well established preclinical model using random bred dogs. The first 3 questions relate to host versus graft reactions and the design of conditioning programs, and the fourth addresses a complication commonly seen after successful engraftment, graft versus host disease (GVHD). With regard to host versus graft "resistance", we plan to extend our previous studies on the graft enhancing ability of a monoclonal antibody (MAb) directed against CD44. This will include investigations of other anti-CD44 MAbs which, in part, have better cross-reactivity with human cells. We are cloning the gene coding for canine CD44; once sequencing of the cDNA is completed we will attempt to generate products from sub full length clones. These products could be used to determine which of the reactive epitopes is important in resistance to marrow grafts. Other MAbs directed against the leukocyte adhesion family of antigens may be investigated. Restriction fragment length polymorphism analyses of DLA class I and II antigens enable us to ask questions about the role of these antigens in graft resistance in unrelated marrow grafts MAbs to canine natural killer (NK) antigens will become available and will permit us to investigate the role of NK cells in engraftment or resistance. Certain new immunosuppressive agents will be evaluated for their ability to overcome resistance. Results of these studies are important for extending marrow transplantation to include more HLA-nonidentical and unrelated transplant recipients. We plan to explore novel conditioning regiments using MAbs coupled to short lived radioactive isotopes which deposit their energy within a narrow radius. By targeting the radiation with the help of a MAb we hope to avoid the toxicity generally seen with high-dose TBI programs. Also, the more intensive conditioning achieved with this approach is likely to set the stage for more successful application of T-cell depleted marrow grafts. Also we plan to develop improved TBI regimens. We will compare the toxicity and immunosuppressive properties of fractionated and single-dose TBI delivered at high dose rates. These studies have obvious implications for the design of clinical conditioning programs. Finally, we propose to investigate new immunosuppressive agents for prevention and treatment of acute GVHD in dogs. Promising new approaches may then be explored clinically, initially in the setting of steroid- resistant acute GVHD.

我们建议研究骨髓领域的 4 个重要问题 移植和全身照射（TB1）。 这些问题的答案 问题与用于治疗的人类骨髓移植有关 患有恶性和非恶性血液病的患者。 我们 计划在一个完善的临床前模型中进行研究 随机饲养的狗。 前 3 个问题与宿主与移植物有关 反应和调节程序的设计，以及第四个地址 成功植入后常见的并发症，移植物与 宿主疾病（GVHD）。 关于宿主对移植物的“抵抗力”，我们计划扩大我们的研究范围 单克隆抗体移植增强能力的前期研究 (MAb) 针对 CD44。 这将包括对其他方面的调查 抗 CD44 单克隆抗体在一定程度上与人类具有更好的交叉反应性 细胞。 我们正在克隆编码犬CD44的基因；一旦测序 cDNA 已完成，我们将尝试从子完整中生成产物 长度克隆。 这些产品可用于确定哪些 反应性表位对于骨髓移植的抵抗力很重要。 其他单克隆抗体 针对白细胞粘附家族的抗原可能是 调查了。 DLA限制性片段长度多态性分析 I 类和 II 类抗原使我们能够提出有关这些抗原的作用的问题 犬无关骨髓移植单克隆抗体中移植物抗性中的抗原 自然杀伤（NK）抗原将变得可用，并使我们能够 研究 NK 细胞在植入或抵抗中的作用。 某些新 将评估免疫抑制剂的克服能力 反抗。 这些研究的结果对于延长骨髓很重要 移植包括更多 HLA 不相同和不相关的移植 收件人。 我们计划探索使用单克隆抗体与短期结合的新型调理方案 活的放射性同位素将能量储存在狭窄的范围内 半径。 通过在单克隆抗体的帮助下瞄准辐射，我们希望避免 高剂量 TBI 治疗中常见的毒性。 还有，越 通过这种方法实现的强化调节可能会设定 阶段，以更成功地应用 T 细胞耗尽的骨髓移植物。 我们还计划开发改进的 TBI 治疗方案。 我们将比较 分次剂量和单剂量的毒性和免疫抑制特性 TBI 以高剂量率进行。 这些研究具有明显的意义 用于临床调理方案的设计。 最后，我们建议研究新的免疫抑制剂 犬急性GVHD的预防和治疗。 有希望的新方法 然后可以进行临床探索，最初是在类固醇的背景下 耐药急性GVHD。