Intrathymic administration of hematopoietic progenitor cells enhances T cell reconstitution in ZAP-70 severe combined immunodeficiency
Intrathymic administration of hematopoietic progenitor cells enhances T cell reconstitution in ZAP-70 severe combined immunodeficiency
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DOI：
10.1073/pnas.0504268102
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发表时间：
2005-09-20
影响因子：
11.1
通讯作者：
Taylor, N
中科院分区：
文献类型：
--
作者：
Adjali, O;Vicente, RR;Taylor, N
重症联合免疫缺陷（SCID）患者存在机会性感染，这些感染在婴儿期几乎普遍致命。这些患者的主要治疗方法是异基因造血干细胞（HSC）移植，但持续的多克隆T细胞重建往往不能令人满意。虽然移植通常是通过静脉注射HSC进行的，但我们假设胸腺内策略更上级。事实上，几个祖细胞群体不能归巢到胸腺，T细胞分化的主要部位，并且似乎存在胸腺对祖细胞输入难治的广泛时间段。为了验证这一假设，将未融合的ZAP-70缺陷型SCID小鼠胸腺内注射WT骨髓祖细胞，这一过程无需手术干预。在胸腺内注射HSC后，T细胞分化更快，移植后4周检测到成熟的胸腺细胞。胸腺内注射HSC还导致显著更高数量的外周T细胞、增加的初始T细胞百分比和更多样化的T细胞受体库。此外，胸腺内移植后的T细胞重建后，获得10倍少的供体HSC注射。因此，这种胸腺内移植方法可以通过增强T细胞重建来改善SCID患者的结果。
Patients with severe combined immunodeficiency (SCID) present with opportunistic infections that are almost universally fatal in infancy. The mainstay treatment for these patients is allogeneic hematopoietic stem cell (HSC) transplantation, but sustained polyclonal T cell reconstitution is too often unsatisfactory. Although transplantation is conventionally performed by i.v. administration of HSC, we hypothesized that an intrathymic strategy would be superior. Indeed, several progenitor cell populations are incapable of homing to the thymus, the major site of T cell differentiation, and it appears that there are extensive time periods during which the thymus is refractory to progenitor cell import. To test this hypothesis, nonconclitioned infant ZAP-70-deficient SCID mice were intrathymically injected with WT bone marrow progenitor cells, a procedure accomplished without surgical intervention. Upon intrathymic HSC injection, there was a more rapid T cell differentiation, with mature thymocytes detected by 4 weeks after transplantation. Intrathymic injection of HSC also resulted in Significantly higher numbers of peripheral T cells, increased percentages of naive T cells, and more diverse T cell receptor repertoires. Moreover, T cell reconstitution after intrathymic transplantation was obtained after injection of 10-fold fewer donor HSC. Thus, this intrathymic transplantation approach may improve the outcome of SCID patients by enhancing T cell reconstitution.