Simpson David
North Shore Hospital, PB 93-503, Takapuna, Auckland 1309, New Zealand.
BioDrugs. 2003;17(3):147-54. doi: 10.2165/00063030-200317030-00001.
Graft versus host disease (GVHD) remains the main barrier to successful allogeneic bone marrow transplant outcomes. Depletion of graft T cells is an effective way of reducing the incidence of acute and chronic GVHD, and a variety of methods have been used to achieve this depletion. Donor CD8+ T cells seem to be the critical effector cells; GVHD is reduced when the depletion process eliminates these cells, but not when CD4 cells are targeted alone. However, despite the successful reduction in GVHD, transplant outcomes are usually inferior with T-cell depleted transplants, because of increased graft failure, infections and relapse. Alternative approaches are needed. In vivo T-cell depletion, using antithymocyte globulin (ATG) as part of the conditioning regimen, seems an attractive option. Pre-transplant ATG lingers in the bone marrow to deplete engrafting donor T cells, but also depletes host T cells to prevent graft rejection and allow de-escalation of the conditioning regimen. It also avoids the need for graft manipulation with its associated costs, need for expertise and CD34+ cell loss. The efficacy of pre-transplant horse ATG remains anecdotal but it has been reported to modestly lower GVHD in single arm studies. Rabbit ATG has been studied in prospective randomised trials. There is evidence of a dose-response effect in reducing GVHD; however, there was no improvement in outcome, because of increased mortality associated with infection. In contrast, pre-transplant alemtuzumab (campath-1H) or an earlier version of this molecule (campath-1G), which target CD52+ cells, do appear to be effective in reducing both acute and chronic GVHD. There is speculation that this is not solely due to the effect of campath on T cells but that it may also be due to the elimination of host antigen-presenting cells (APC), which seem to be important in GVHD pathogenesis. Host APC are more efficient at expressing endogenous and exogenous host antigens on class I MHC to donor CD8+ cells than donor APC, which need to cross-prime exogenous antigen. Campath-1G eliminates host dendritic cells by the time of graft infusion, supporting this as a possible mechanism of action. Pre-transplant alemtuzumab has not yet been studied in a prospective randomised study, and this is required to quantify any benefit on outcome; despite this, published studies do show cause for optimism.
移植物抗宿主病（GVHD）仍然是异基因骨髓移植成功的主要障碍。去除移植物中的T细胞是降低急性和慢性GVHD发生率的有效方法，人们已采用多种方法来实现这种去除。供体CD8 + T细胞似乎是关键效应细胞；当去除过程消除这些细胞时，GVHD会降低，但仅针对CD4细胞时则不会。然而，尽管GVHD成功降低，但由于移植失败、感染和复发增加，T细胞去除的移植结果通常较差。需要其他方法。在预处理方案中使用抗胸腺细胞球蛋白（ATG）进行体内T细胞去除似乎是一个有吸引力的选择。移植前的ATG会在骨髓中停留以去除植入的供体T细胞，但也会去除宿主T细胞以防止移植排斥并允许降低预处理方案的强度。它还避免了对移植物进行操作及其相关成本、专业知识需求和CD34 +细胞损失。移植前马ATG的疗效仍只是传闻，但在单臂研究中据报道它能适度降低GVHD。兔ATG已在前瞻性随机试验中进行了研究。有证据表明在降低GVHD方面存在剂量反应效应；然而，由于与感染相关的死亡率增加，结果并未得到改善。相比之下，移植前的阿仑单抗（campath - 1H）或该分子的早期版本（campath - 1G），它们靶向CD52 +细胞，似乎在降低急性和慢性GVHD方面都有效。有人推测这不仅是由于campath对T细胞的作用，还可能是由于消除了宿主抗原呈递细胞（APC），而宿主抗原呈递细胞在GVHD发病机制中似乎很重要。宿主APC在将内源性和外源性宿主抗原呈递给供体CD8 +细胞的I类MHC上比供体APC更有效，供体APC需要交叉呈递外源性抗原。在移植输注时，campath - 1G会消除宿主树突状细胞，这支持了这是一种可能的作用机制。移植前阿仑单抗尚未在前瞻性随机研究中进行研究，而这是量化其对结果的任何益处所必需的；尽管如此，已发表的研究确实显示出乐观的理由。
