Mediterranean Institute of Hematology, IME Foundation, Policlinico di Tor Vergata, Rome, Italy.
Haematologica. 2009 Oct;94(10):1415-26. doi: 10.3324/haematol.2008.003129. Epub 2009 Jul 16.
Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood.
The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor.
Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro.
Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.
重型地中海贫血可以通过异体造血干细胞移植治愈。约 10%接受移植的地中海贫血患者会出现持续混合嵌合体，但这种现象的生物学机制尚未完全了解。
研究了 8 例持续混合嵌合体患者和 5 例完全供者嵌合体患者外周血中产生白细胞介素-10 的 T 细胞的存在情况。然后，对 1 例接受 HLA 匹配无关供者造血干细胞移植后出现稳定的红细胞/淋巴细胞嵌合体的持续混合嵌合体患者进行了详细的特征描述，通过 T 细胞克隆分析了其效应和调节性 T 细胞库。
持续混合嵌合体患者的外周血单个核细胞产生的白细胞介素-10 水平高于完全供者嵌合体患者或正常供者的细胞。从一名选择的持续混合嵌合体患者的外周血中可以分离出宿主和供体来源的 T 细胞克隆。与针对宿主或供体同种异体抗原的效应 T 细胞克隆一起，还鉴定出具有 1 型调节细胞特征性细胞因子分泌谱的调节性 T 细胞克隆，其频率较高。供体和宿主来源的 1 型调节性细胞克隆均能够在体外抑制供体或宿主来源的效应 T 细胞的功能。
总的来说，这些结果表明白细胞介素-10 和 1 型调节性细胞与持续混合嵌合体有关，并可能在体内维持长期耐受中发挥重要作用。这些数据为嵌合体患者外周耐受的机制提供了新的见解，并支持在造血干细胞移植后使用调节性 T 细胞进行细胞治疗。
