Donor fibroblast chimerism in the pathogenic fibrotic lesion of human chronic graft-versus-host disease
Donor fibroblast chimerism in the pathogenic fibrotic lesion of human chronic graft-versus-host disease
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DOI：
10.1167/iovs.05-0227
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Kuwana, M
中科院分区：
文献类型：
--
作者：
Ogawa, Y;Kodama, H;Kuwana, M
目的。组织萎缩和过度纤维化是同种异体造血干细胞移植后慢性移植物抗宿主病（GVHD）的显著组织学特征，但其潜在机制尚不清楚。目前的研究旨在调查慢性gvhd患者致病性纤维化部位成纤维细胞的增加是否源于移植供体细胞。对9例慢性GVHD患者进行泪腺活检。用荧光素原位杂交（FISH）和原位杂交（ISH）检测到的男性特异性序列作为7名接受男性供体移植的女性患者供体细胞的标记物。从泪腺活检标本中产生原代成纤维细胞培养物，并检查受体和供体之间的遗传标记是否不匹配。在接受性别不匹配移植的7名女性患者的泪腺标本中，通过FISH检测y染色体，在纤维化病变中积累的CD34（+）成纤维细胞中有13.4%至26.7%来自供体。在泪腺成纤维细胞中也检测到男性特异性mRNA。从4名慢性GVHD患者身上培养出原代泪腺成纤维细胞，并进一步检查受体和供体之间的遗传标记是否不匹配。结果，通过检测y染色体序列和供者特异性微卫星遗传标记，证实了成纤维细胞的供者来源。这些发现共同表明慢性GVHD患者泪腺中积累的CD34（+）成纤维细胞的嵌合状态。源自循环供体前体的成纤维细胞可能参与了这些患者的过度纤维化。
PURPOSE. Tissue atrophy and excessive fibrosis are prominent histologic features of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation, but the underlying mechanism remains unknown. The current study was undertaken to investigate whether the increase in fibroblasts at the site of pathogenic fibrosis originated from transplanted donor cells in patients with chronic GVHD.METHODS. Lacrimal gland biopsy specimens were obtained from nine patients with chronic GVHD. The male-specific sequences detected by fluorescein in situ hybridization (FISH) and in situ hybridization (ISH) were used as markers for the donor cells in seven female patients who had received a transplant from male donors. Primary fibroblast cultures were generated from lacrimal gland biopsy specimens and examined for mismatched genetic markers between recipients and donors.RESULTS. In lacrimal gland specimens obtained from seven female patients who received a sex-mismatched transplant, 13.4% to 26.7% of CD34(+) fibroblasts that accumulated in the fibrotic lesion were donor derived, as determined by FISH for the Y-chromosome. The male-specific mRNA was also detected in the lacrimal gland fibroblasts by ISH. Primary lacrimal gland fibroblast cultures were generated from four patients with chronic GVHD and further examined for mismatched genetic markers between recipients and donors. As a result, the presence of donor origin of the fibroblasts was demonstrated by detecting the Y-chromosome sequence and donor-specific microsatellite genetic markers.CONCLUSIONS. These findings together indicate the chimeric status of accumulated CD34(+) fibroblasts in the lacrimal gland of patients with chronic GVHD. Fibroblasts originating from circulating donor-derived precursors may participate in the excessive fibrosis in these patients.