Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response
Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response
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DOI：
10.1053/bbmt.2003.50027
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发表时间：
2003-04-01
影响因子：
4.3
通讯作者：
Korngold, R
中科院分区：
文献类型：
--
作者：
Jones, SC;Murphy, GF;Korngold, R
在异基因造血细胞移植（HCT）后，移植物抗宿主病（GVHD）和白血病复发之间的高度负相关性要求采取计算的措施以减少GVHD病理，同时保留移植物抗白血病（GVL）效应。我们试图确定供体CD 4（+）CD 25（+）调节性T细胞是否可以控制正在进行的GVHD，从而提供允许同种异体反应性抗宿主反应开始的初始时间窗，目的是最有效地消除残留的白血病细胞。在单倍体相合的C3 H-->（B6 xC 3 H）F-1模型中，在HCT后早期（第2天）通过输注供体CD 4（+）CD 25（+）细胞，可以跨越主要组织相容性复合体屏障，预防致死性GVHD。然而，成功调节需要在高剂量白细胞介素-2存在下由受体细胞刺激供体CD 4（+）CD 25（+）T细胞的体外扩增。相比之下，在主要组织相容性复合物匹配、次要组织相容性抗原不同、CD 8介导的B10.BR-->CBA GVHD模型中，通过单次输注新鲜分离的供体CD 4（+）CD 25（+）细胞，可以完全预防致死性疾病，最迟在HCT后10天给药。重要的是，这种晚期调节作用仅需要效应CD 8：CD 4（+）CD 25（+）T细胞的3：1比例，表明延迟输注CD 4（+）CD 25（+）细胞以控制跨越次要组织相容性抗原屏障的GVHD的强大潜力。此外，这种调节不干扰造血区室的完全和持久的供体植入。最重要的是，第10天将供体CD 4（+）CD 25（+）细胞输注到已经用MMCBA 6髓性白血病细胞系攻击的CBA HCT受体中，尽管减少了致死性GVHD，但没有阻断有效的GVL应答。这些结果表明，移植后立即输注供体CD 4（+）CD 25（+）T细胞可以改善GVHD的发展，而不牺牲足够的GVL效应。(C)2003年美国血液和骨髓移植学会。
After allogeneic hematopoietic cell transplantation (HCT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse requires that calculated measures be taken to reduce GVHD pathology while retaining the graft-versus-leukemia (GVL) effect. We sought to determine whether donor CD4(+)CD25(+) regulatory T cells could control ongoing GVHD, thereby providing an initial window of time in which the alloreactive anti-host response is permitted to begin, with the intent of most effectively eliminating residual leukemia cells. Prevention of lethal GVHD by infusion of donor CD4(+)CD25(+) cells early after HCT (day 2) was achieved across a major histocompatibility complex barrier in the haploidentical C3H-->(B6xC3H)F-1 model. However, in vitro expansion of donor CD4(+)CD25(+) T cells, stimulated by recipient cells in the presence of high-dose interleukin-2, was required for successful regulation. In contrast, in the major histocompatibility complex-matched, minor histocompatibility antigen-disparate, CD8-mediated B10.BR-->CBA GVHD model, lethal disease could be completely prevented by a single infusion of freshly isolated donor CD4(+)CD25(+) cells administered as late as 10 days after HCT. Of importance, this late regulatory effect required only a 3:1 ratio of effector CD8:CD4(+)CD25(+) T cells, indicating a strong potential for the delayed infusion of CD4(+)CD25(+) cells to control GVHD across minor histocompatibility antigen barriers. Furthermore, this regulation did not interfere with complete and lasting donor engraftment of the hematopoietic compartment. Of most significance, the day 10 infusion of donor CD4(+)CD25(+) cells into CBA HCT recipients that had been challenged with the MMCBA6 myeloid leukemia cell line did not block an effective GVL response, despite reducing lethal GVHD. These results suggest that donor CD4(+)CD25(+) T cells infused soon after transplantation can ameliorate the development of GVHD without sacrificing a sufficient GVL effect.(C) 2003 American Society for Blood and Marrow Transplantation.