Hacein-Bey S, Gross F, Nusbaum P, Yvon E, Fischer A, Cavazzana-Calvo M
INSERM U429, Hôpital Necker-Enfants-Malades, 149 rue de Sèvres, 75015 Paris, France.
Pathol Biol (Paris). 2001 Feb;49(1):57-66. doi: 10.1016/s0369-8114(00)00002-x.
X-linked severe combined immunodeficiency (SCID-X1) is a recessive hereditary disorder in which early T and Natural Killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common gamma c chain that participates in several cytokine receptors including the interleukin-2 (Il-2), Il-4, Il-7, Il-9, Il-15 receptors. SCID-X1 offers a reliable model for gene therapy as it is a lethal condition that is, in many cases, curable by allogeneic bone marrow transplantation. We have shown that retrovirus-mediated transfer of the gamma c cDNA induced gamma c chain expression and restored the function of the high-affinity IL-2 receptor on SCI-X1 EBV-transformed B-cell lines. We have the designed culture conditions to study NK-cell and T-cell development of CD34+ hematopoietic progenitor cells. In the culture systems, gamma c transduced CD34+ marrow cells from two SCID-X1 patients were able to mature into CD56+ and/or CD16+ NK cells and into CD4+ TCR alpha beta+ T cells. These preclinical results set the basis for a clinical study of ex-vivo gamma c gene transfer into CD34+ cells from SCID-X1 patients.
X连锁重症联合免疫缺陷病（SCID-X1）是一种隐性遗传性疾病，其中早期T淋巴细胞和自然杀伤（NK）淋巴细胞的发育受阻。这种遗传性疾病是由参与多种细胞因子受体（包括白细胞介素-2（Il-2）、Il-4、Il-7、Il-9、Il-15受体）的共同γ链突变引起的。SCID-X1为基因治疗提供了一个可靠的模型，因为它是一种致命疾病，在许多情况下可通过异基因骨髓移植治愈。我们已经表明，逆转录病毒介导的γc cDNA转移可诱导γc链表达，并恢复SCI-X1 EBV转化的B细胞系上高亲和力IL-2受体的功能。我们设计了培养条件来研究CD34+造血祖细胞的NK细胞和T细胞发育。在培养系统中，来自两名SCID-X1患者的γc转导CD34+骨髓细胞能够成熟为CD56+和/或CD16+NK细胞以及CD4+TCRαβ+T细胞。这些临床前结果为对SCID-X1患者的CD34+细胞进行体外γc基因转移的临床研究奠定了基础。
