CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation
CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone marrow of patients with multiple myeloma following allogeneic stem cell transplantation
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DOI：
10.3324/haematol.11897
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发表时间：
2008-02-29
期刊：
影响因子：
10.1
通讯作者：
Kroger, Nicolaus
中科院分区：
文献类型：
--
作者：
Atanackovic, Djordje;Cao, Yanran;Kroger, Nicolaus
背景人类骨髓中具有免疫抑制作用的CD 4（+）CD 25（+）FOXP 3（+）T调节细胞（Treg）的数量和功能尚不清楚，而且还不清楚骨髓中的Treg在异基因干细胞移植后是否能够再生。这是特别令人惊讶的，因为骨髓代表T细胞应答的主要引发位点，Treg在预防T细胞介导的移植物抗宿主病和促进肿瘤逃避T细胞依赖性免疫监视中起重要作用。我们在异基因干细胞移植前后对健康供体以及多发性骨髓瘤患者的骨髓和外周血Treg进行了首次研究。结果我们发现，在异基因移植后，供体来源的CD 4（+）CD 25（+）FOXP 3（+）Treg比常规CD 4（+）T细胞扩增更快，导致Treg在缺乏相关胸腺功能的移植患者的骨髓中积累。同种异体干细胞移植后骨髓瘤患者的Treg优选由CD 45 RA（-）CCR 7（-）记忆T细胞组成，并含有低数量的T细胞受体切除周期，表明Treg确实在胸腺外扩张了。重要的是，骨髓驻留Treg的新诊断和骨髓瘤患者异基因干细胞移植后表达高水平的转化生长因子β和细胞毒性T淋巴细胞抗原4，并表现出较强的抑制functions.ConclusionsWe建议，异基因干细胞移植提供了一个短暂的，但重要的机会窗口CDS+ T细胞之前的免疫抑制Treg集旺盛的再生。移植后，骨髓驻留Treg可能有助于抑制移植物抗宿主病，但也可能破坏多发性骨髓瘤的持续免疫控制。
BackgroundVery little is known about the number and function of immunosuppressive CD4(+)CD25(+)FOXP3(+) T regulatory cells (Treg) in the human bone marrow and it is unclear whether bone marrow-residing Treg are capable of regenerating following allogeneic stem cell transplantation. This is particularly surprising since the bone marrow represents a major priming site for T-cell responses and Treg play important roles in the prevention of T-cell-mediated graft-versus-host disease and in promoting tumor escape from T-cell-dependent immunosurveillance.Design and MethodsApplying flow cytometry, real-time polymerase chain reaction, and functional assays, we performed the first study on bone marrow and peripheral blood Treg in healthy donors as well as multiple myeloma patients before and after allogeneic stem cell transplantation.ResultsWe found that, following the allogeneic transplantation, donor-derived CD4(+)CD25(+)FOXP3(+) Treg expanded faster than conventional CD4(+) T cells, leading to an accumulation of Treg in the bone marrow of transplanted patients who lack relevant thymic function.The reconstituted bone marrow-residing CD4(+)CD25(+)FOXP3(+) Treg of myeloma patients after allogeneic stem cell transplantation consisted preferably of CD45RA(-)CCR7(-) memory T-cells and contained low numbers of T-cell receptor excision cycles, indicating that Treg had indeed expanded outside the thymus. Importantly, bone marrow-residing Treg of newly diagnosed and myeloma patients after allogeneic stem cell transplantation expressed high levels of transforming growth factor beta and cytotoxic T-lymphocyte antigen 4, and showed a strong inhibitory function.ConclusionsWe suggest that allogeneic stem cell transplantation provides a short but significant window of opportunity for CDS+ T cells before an exuberant regeneration of immunosuppressive Treg sets in. Later after transplantation, bone marrow-residing Treg probably contribute to suppressing graftversus-host disease but may also undermine persistent immune control of multiple myeloma.