Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice
Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice
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DOI：
10.1038/3233
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发表时间：
1998-11-01
期刊：
影响因子：
82.9
通讯作者：
Brenner, MK
中科院分区：
文献类型：
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作者：
Brown, MP;Topham, DJ;Brenner, MK
CD40配体的遗传缺陷（X连锁高IGM综合征）的特征是免疫球蛋白同种型切换和细胞介导的免疫力的严重缺陷失败。为了测试基因转移疗法纠正这种疾病的潜力，我们用含有鼠CD40配体（CD40L）cDNA的逆转录病毒载体转导鼠骨髓或胸腺细胞，并将其注入CD40L（/ - ）小鼠。这些小鼠的转基因的低水平构成表达也刺激了体液和细胞免疫功能。然而，随着随访的扩展，有12只经过治疗的小鼠中有12例出现了T-淋巴结增生性疾病，从淋巴细胞的多克隆增加到涉及多个器官的公开单克隆T淋巴细胞淋巴瘤。我们的发现表明，构成性（而不是严格调节）CD40L的低水平表达可以在开发T淋巴细胞中产生异常的增殖反应，这显然是通过CD40L（+）和TCR alpha beta（+）CD40（+）CD40（+）胸腺细胞之间的异常相互作用。当前的基因疗法方法可能证明不适合涉及在增殖性级联反应中基本位置高度调节基因的疾病。
Inherited deficiency of the CD40 ligand (X-linked hyper-IgM syndrome) is characterized by failure of immunoglobulin isotype switching and severe defects of cell-mediated immunity. To test the potential for gene transfer therapy to correct this disorder, we transduced murine bone marrow or thymic cells with a retroviral vector containing the cDNA for the murine CD40 ligand (CD40L) and injected them into CD40L(-/-) mice.; Even low-level, constitutive expression of the transgene stimulated humoral and cellular immune functions in these mice. With extended follow-up, however, 12 of 19 treated mice developed T-lymphoproliferative disorders, ranging from polyclonal increases of lymphoblasts to overt monoclonal T-lymphoblastic lymphomas that involved multiple organs. Our findings show that constitutive (rather than tightly regulated), low-level expression of CD40L can produce abnormal proliferative responses in developing T lymphocytes, apparently through aberrant interaction between CD40L(+) and TCR alpha beta(+)CD40(+) thymocytes. Current methods of gene therapy may prove inappropriate for disorders involving highly regulated genes in essential positions in proliferative cascades.