Prevention and Treatment of Graft-Versus-Host Disease

项目3移植物抗宿主病的预防和治疗：该项目的目标是改善 更加有效的预防和治疗异基因造血细胞移植后的生存 急性移植物抗宿主病(GVHD)。目标1旨在通过以下途径预防移植物抗宿主病 预防性口服局部活性糖皮质激素，但对全身影响不大。各别 第二阶段临床试验将在清髓性和非清髓性患者中进行 HCT前的调理方案。这些研究将检验预防性给药的假设 倍氯米松可显著降低胃肠道移植物抗宿主病的发生率 肠道，可能还有其他靶器官。目标2旨在减少类固醇的数量 在HCT后出现这种并发症的患者中，需要控制GVHD的治疗。患者 采用清髓调理方案的HCT后发生急性移植物抗宿主病将采用小剂量治疗 Alemtuzumab用于测试在注射抗体后T细胞耗尽将会 加速疾病的解决，并允许更快地停止类固醇治疗，而不需要 增加了机会性感染的风险。HCT后发生移植物抗宿主病的患者 清髓性调节方案将用小剂量的甲氨蝶呤治疗，以检验以下假设： 这种药物对供者T细胞的影响将加速疾病的解决，并允许更快 停用类固醇治疗，不增加复发恶性肿瘤的风险。在目标3中，第一阶段和 将进行第二阶段临床试验，以测试注射CD28特异性抗体的假设 对治疗或预防急性移植物抗宿主病有效，正如先前的实验室研究所表明的那样。病人 患有目前无法控制的GVHD的患者将进入I期临床 审判。如果第一阶段的研究结果令人鼓舞，则将进行第二阶段的研究，以测试 注射该抗体可以预防人类移植物抗宿主病。 与公共卫生的相关性：该项目中的研究可能会导致开发更有效的 预防或治疗血液或骨髓中可能发生的有害免疫反应的方法 移植被用于治疗白血病、淋巴瘤、骨髓瘤和其他相关疾病。成功 这种方法的发展将提高血液或骨髓移植的安全性和适用性。 用于治疗这些疾病。‘

Project 3 Prevention and Treatment of Graft-versus-host Disease: The goal of this project is to improve survival after allogeneic hematopoietic cell transplantation (HCT) by more effective prevention and treatment of acute graft-versus-host disease (GVHD). Aim 1 is directed toward prevention of GVHD through prophylactic oral administration of a topically active glucocorticoid that has little systemic effect. Separate phase II clinical trials will be carried out among patients who have myeloablative and non-myeloablative conditioning regimens before HCT. These studies will test the hypothesis that prophylactic administration of beclomethasone diproprionate can greatly decrease the incidence of GVHD involving the gastro-intestinal tract and possibly other target organs as well. Aim 2 is directed toward decreasing the amount of steroid treatment needed to control GVHD among patients who develop this complication after HCT. Patients who develop acute GVHD after HCT with a myeloablative conditioning regimen will be treated with low-dose alemtuzumab to test the hypothesis that depletion of T cells after administration of the antibody will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of opportunistic infections. Patients who develop GVHD after HCT with a non- myeloablative conditioning regimen will be treated with low-dose methotrexate to test the hypothesis that the effects of this drug on donor T cells will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of recurrent malignancy. In Aim 3, phase I and phase II clinical trials will be carried out to test the hypothesis that administration of a CD28-specific antibody is effective for treatment or prevention of acute GVHD, as suggested by previous laboratory studies. Patients with GVHD that cannot be controlled by currently available treatments will be enrolled in a phase I clinical trial. If results of the phase I study are encouraging, then a phase II study will be carried out to test whether administration of the antibody can prevent GVHD in humans. Relevance to Public Health: The studies in this project could lead to the development of more effective methods for preventing or treating harmful immune reactions that can occur when blood or marrow transplantation is used to treat leukemia, lymphoma, myeloma and other related disorders. Successful development of such methods would improve the safety and applicability of blood or marrow transplantation for treatment of these diseases. '