Novel Approaches to GHVD Prevention

虽然HSCT是一种有效的治疗方法，但它的使用与GVHD等重大风险相关。减少GVHD的战略已经进行了多次试验，但努力并不完全有效，需要采取新的方法。甲氨蝶呤的细胞毒性是钙调神经磷酸酶抑制的重要辅助物质，但其固有毒性延长了恢复计数的时间，增加了毒性。这个项目的目标是研究两种新的方法来 GVHD控制。第一种是利用西罗莫司和他克莫司之间的协同作用。通过使用低剂量的这些药物，有可能控制移植物抗宿主病并降低与移植相关的死亡率。在高危患者中进行的初步研究表明，GVHD控制前景看好，毒性最小。第二种方法结合了两种有希望的匹配同胞HSCT的方法：1)使用动员的PBSC作为骨髓干细胞的替代品，以加快植入和 2)T细胞耗竭(TCD)降低GVHD。PBSCT的随机试验表明，更快的植入、更多的移植物-v-白血病(GVL)和更完全的免疫恢复可能会提高存活率。然而，患急性尤其是慢性移植物抗宿主病的风险更高。对TCD的兴趣减弱了，因为GVL的丧失似乎是一个严重的限制。供者淋巴细胞输注可恢复移植物抗宿主病，但有发生移植物抗宿主病的风险。初步研究表明，去除CD8+T细胞的PBSC是可行的，具有良好的植入性和可控性GVHD。这一观察结果导致假设，使用CD8耗尽的PBSC的PBSCT将通过保持GVHD较少的未处理PBSCT的好处而改善预后。这项建议的具体目的是：1)研究西罗莫司、他克莫司在无血缘关系的供者和家庭成员移植中与小剂量甲氨蝶呤或不同剂量甲氨蝶呤的联合应用。目标是消除MTX并保持对GVHD的控制 和GVL；2)研究在配对同胞和非血缘关系供者移植中使用镍珠联抗CD8产品(CD8-HDM)去除CD8+T细胞的PBSCT；以及3)研究非清髓性移植后西罗莫司、他克莫司和小剂量甲氨蝶呤的使用。所有这些项目都将与生活质量、嵌合体和免疫恢复的研究有关。数据将从经过充分研究的队列中收集，以促进 趋化因子的使用，以及在移植物抗宿主病中重要的次要组织相容性抗原的鉴定。长期计划是为第二阶段随机试验提供平台，并根据在其他项目中获得的数据进行干预。

While HSCT is an effective therapy, its use is associated with substantial risks, such as GVHD. Strategies to reduce GVHD have been the subject of numerous trials, but efforts have been incompletely effective and novel approaches are needed. The cytotoxicity of methotrexate is an important adjunct to calcineurin inhibition, but its intrinsic toxicity prolongs time to count recovery and increases toxicity. The objective of this project is to study two new approaches to GVHD control. The first takes advantage of the synergism between of siro!imus and tacrolimus. By using low doses of these drugs, it may be possible to control GVHD and to reduce transplant-related mortality. Pilot studies in high risk patients show a promising GVHD control and minimal toxicity. The second combines two promising approaches in matched sibling HSCT: 1) the use of mobilized PBSC as an alternative to marrow stem cells to speed engraftment and 2) T cell depletion (TCD) to reduce GVHD. Randomized trials of PBSCT show that survival can be improved perhaps due to more rapid engraftment, more graft-v-leukemia (GVL), and more complete immunologic recovery. However, there is a higher risk of acute and especially chronic GVHD. Interest in TCD waned, as it appeared that the loss of GVL was a serious limitation. GVL can be restored with donor lymphocyte infusions, but at significant risk of GVHD. Preliminary studies show that depletion of PBSC of CD8+ T cells is feasible with an excellent engraftment and controllable GVHD. This observation leads to the hypothesis that PBSCT using CD8 depleted PBSC will result in improved outcomes by maintaining the benefits of unmanipulated PBSCT with less GVHD. The specific aims of this proposal are: 1) to perform studies of the combination of sirolimus, tacrolimus, with or without low dose methotrexate in unrelated donor and family-member transplantation. The goal will be to eliminate MTX and maintain GVHD control and GVL; 2) to study PBSCT depleted of CD8+ T cells using a nickel bead-conjugated anti-CD8 product (CD8-HDM) in matched sibling and unrelated donor transplantation; and 3) to study the use of sirolimus, tacrolimus, and low dose methotrexate after non-myeloablative transplantation. All of these projects will be associated with studies of quality of life, chimerism, and immune recovery. Data will be collected from a well-studied cohort to facilitate correlations of chemokine use, and identification of minor histocompatibility antigens that are important in GVHD. Long-term plans are to provide the platform for phase II randomized trials as well as interventions based on data in obtained in the other projects.