In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation.
In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation.
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宿主调节性T细胞的原位激活和扩增：在主要组织相容性复合体匹配的同种异体造血细胞移植中增强供体嵌合和稳定植入的新方法。
DOI：
10.1016/j.bbmt.2009.03.011
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Levy,RobertB
中科院分区：
文献类型：
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作者：
Shatry,Alwi;Levy,RobertB
宿主抗供体效应T细胞代表了同种异体供体造血祖细胞和干细胞成功植入的主要障碍。在这里，IL-2和抗IL-2抗体（IAC）的复合物的管理显着增强供体嵌合体早期以及长期植入后，降低强度的条件（RIC）和异基因主要组织相容性复合体（MHC）匹配的造血细胞移植（HCT）。该复合物的给药时机至关重要：HCT后IAC给药比HCT前治疗更有效地促进骨髓移植。供体嵌合体持续至HCT后>6个月。重要的是，如通过四聚体染色评估的，该方法明显抑制了HCT后2至3周宿主抗供体CD 8 T细胞的出现。在HCT后>5个月用供体抗原体内再活化IAC处理的和对照受体后，仅PBS处理的对照骨髓同种异体移植物受体对四聚体结合CD 8细胞有应答。总之，目前的研究结果支持的概念，即在原位HCT后的宿主TcR的瞬时激活和扩展可以探索作为一种新的方法来调节宿主同种异体反应性移植后。有趣的是，在降低强度的条件接受者中直接刺激接受者Treg细胞避免了在该模型中对外源性Treg细胞输注的需要，并且可能代表临床HCT中Treg群体的适应性转移的可行替代方案和/或补充。
Host antidonor effector T cells represent a major barrier to the successful engraftment of allogeneic donor hematopoietic progenitor and stem cells. Here, administration of a complex of IL-2 and anti-IL 2 antibody (IAC) significantly enhanced donor chimerism early as well as long-term engraftment following reduced-intensity conditioning (RIC) and allogeneic major histocompatibility complex (MHC)-matched hematopoietic cell transplant (HCT). Timing of administration of this complex was crucial: administration of IAC post-HCT more efficiently facilitated marrow engraftment than pre-HCT treatment. Donor chimerism persisted to >6 months post-HCT. Importantly, this approach clearly suppressed the emergence of host antidonor CD8 T cells 2 to 3 weeks post-HCT as assessed by tetramer staining. Following in vivo reactivation of IAC-treated and control recipients at >5 months post-HCT with donor antigen, only PBS-treated control marrow allograft recipients responded with tetramer-binding CD8 cells. In total, the present findings support the notion that the transient activation and expansion of host Tregs in situ post-HCT can be explored as a new approach to regulate host alloreactivity posttransplant. Interestingly, direct stimulation of recipient Treg cells in reduced-intensity conditioned recipients obviated a requirement for exogenous Treg cell transfusion in this model and may represent a viable alternative to, and/or complement the adaptive transfer of Treg populations in clinical HCT.