IRRADIATION AND MARROW TRANSPLANTATION

放射治疗和骨髓移植

• 批准号: 2088214
• 负责人: Rainer F. Storb
• 金额: $ 56.99万
• 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/2088214
• 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.

我们建议在骨髓区域调查4个重要问题 移植和全身照射（TB1）。 这些答案 问题与人类骨髓移植有关 患有恶性和非恶性血液疾病的患者。 我们 计划在建立良好的临床前模型中进行研究 随机育种狗。 前3个问题与宿主与移植有关 反应和调节计划的设计以及第四个地址 成功植入后通常看到的一种并发症，移植物与 宿主病（GVHD）。 关于宿主与移植的“阻力”，我们计划扩展我们的 先前关于单克隆抗体的移植物增强能力的研究 （mAb）针对CD44。 这将包括对其他的调查 抗CD44 mAb，部分地与人具有更好的交叉反应性 细胞。 我们正在克隆犬CD44的基因编码；一旦测序 cDNA完成了，我们将尝试从Sub Full生成产品 长度克隆。 这些产品可用于确定哪个 反应性表位对抗骨髓移植物的抗性很重要。 其他mab 针对白细胞粘附家族的抗原可能是 调查。 DLA的限制片段长度多态性分析 I级和II抗原使我们能够问有关这些作用的问题 在无关的骨髓移植物中移植耐药的抗原对犬的抗原 天然杀手（NK）抗原将可用，并将允许我们 研究NK细胞在植入或抗性中的作用。 某些新 免疫抑制剂的克服能力将评估 反抗。 这些研究的结果对于扩展骨髓很重要 移植以包括更多的HLA非病变和无关的移植 收件人。 我们计划使用耦合到短的mABS探索新颖的调理团 活着的放射性同位素将其能量沉积在狭窄的 半径。 通过在mab的帮助下瞄准辐射，我们希望避免 大剂量TBI计划通常可以看到毒性。 另外，越多 通过这种方法实现的密集调理可能会设定 阶段更成功地应用T细胞耗尽的骨髓移植物。 我们还计划开发改进的TBI方案。 我们将比较 分离和单剂量的毒性和免疫抑制特性 TBI以高剂量率交付。 这些研究具有明显的影响 用于设计临床调节计划。 最后，我们建议调查新的免疫抑制剂 狗的急性GVHD的预防和治疗。 有希望的新方法 然后可以在临床上，最初在类固醇的情况下进行探索 抗性急性GVHD。