Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis
Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis
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DOI：
10.1182/blood-2003-03-0707
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发表时间：
2004-02-01
期刊：
影响因子：
20.3
通讯作者：
Markham, AF
中科院分区：
文献类型：
--
作者：
Coletta, PL;Müller, AM;Markham, AF
腺瘤性息肉病大肠杆菌肿瘤抑制基因的种系突变会导致小鼠和人类遗传性肠道肿瘤发生。在这里，我们发现，在 Apc (Min/+) 小鼠中，在 Apc 密码子 850 处携带杂合种系突变，从大约 80 天开始，未成熟和成熟胸腺细胞逐渐丧失，并在 120 天时胸腺完全消退。此外，由于白细胞介素 7 (IL-7) 依赖性 B 细胞祖细胞完全丧失，Apc(Min/+) 小鼠表现出脾脏自然杀伤 (NK) 细胞、未成熟 B 细胞和骨髓中 B 祖细胞的平行消耗。通过对野生型受体进行骨髓移植实验，我们发现移植的 Apc(Min/+) 骨髓细胞的 T 细胞和 B 细胞发育能力似乎正常。相比之下，尽管Apc(Min/+)骨髓微环境支持野生型骨髓的短期重建，但接受移植的Ap(Min/+)动物随后进行了淋巴细胞清除。成纤维细胞集落形成单位 (CFU-F) 集落测定显示，与野生型动物相比，在淋巴细胞清除开始之前，Apc(Min/+) 小鼠骨髓中集落形成间充质祖细胞显着减少。这表明骨髓微环境的改变可能是家族性腺瘤性息肉病模型中观察到的选择性淋巴细胞耗竭的原因。
Germ line mutations in the Adenomatous polyposis coli tumor suppressor gene cause a hereditary form of intestinal tumorigenesis in both mice and man. Here we show that in Apc(Min/+) mice, which carry a heterozygous germ line mutation at codon 850 of Apc, there is progressive loss of immature and mature thymocytes from approximately 80 days of age with complete regression of the thymus by 120 days. In addition, Apc(Min/+) mice show parallel depletion of splenic natural killer (NK) cells, immature B cells, and B progenitor cells in bone marrow due to complete loss of interleukin 7 (IL-7)-dependent B-cell progenitors. Using bone marrow transplantation experiments into wild-type recipients, we have shown that the capacity of transplanted Apc(Min/+) bone marrow cells for T- and B-cell development appears normal. In contrast, although the Apc(Min/+) bone marrow microenvironment supported short-term reconstitution with wild-type bone marrow, Ap(Min/+) animals that received transplants subsequently underwent lymphodepletion. Fibroblast colony-forming unit (CFU-F) colony assays revealed a significant reduction in colony-forming mesenchymal progenitor cells in the bone marrow of Apc(Min/+) mice compared with wild-type animals prior to the onset of lymphodepletion. This suggests that an altered bone marrow microenvironment may account for the selective lymphocyte depletion observed in this model of familial adenomatous polyposis.