AN ANIMAL MODEL OF XSCID--A PRECLINICAL MODEL FOR GENE/CYTOKINE THERAPIES

细胞因子信号在淋巴细胞功能中起重要作用， 发展 这些信号的失调可以阻碍T细胞 发展并导致自身免疫。近年来研究表明 具有突变的细胞因子受体基因的个体表现出严重的 免疫缺陷综合征（XSCID）。许多细胞因子受体由 几条链，其中一些在不同的细胞因子之间共享 受体。这种复杂性使我们很难研究 特异性细胞因子和受体在不同人类疾病状态中的作用。 共同γ链（Gc）是IL-2、IL-4、IL-7、IL-9和IL-15的一部分 受体复合物通过其与激酶和 其他分子，它传递信号的重要淋巴细胞功能。 为了检查GC介导的信号的作用，产生小鼠，其中 通过同源重组使编码Gc的基因失活。 对这些小鼠的检查表明，淋巴细胞的发育是 影响。虽然正常的T细胞群， 与正常胸腺相比，胸腺细胞减少。 此外，我们观察到， 胸腺中CD 4/CD 8比率的改变表明T细胞选择 受到了影响外周血T细胞也受到影响，在GC缺乏 小鼠CD 8+细胞数量持续偏低，而CD 4+细胞数量持续偏低。 随着年龄的增长而增加，这表明正常机制的缺陷， 自身反应性细胞的外周缺失（凋亡）。而外围 T细胞在功能上不能对TCR接合做出反应， 胸腺前体响应TCR接合而增殖。等 研究结果提示细胞因子在差异调节T细胞中的作用， 反应性与T细胞无反应性。B细胞的发育和功能是 也受到抑制。未来的实验将致力于培育 GC-缺陷进入表达编码自身反应性抗原的转基因的小鼠 受体。这种动物模型的开发应该是重要的， 了解细胞因子在自身免疫性疾病和淋巴细胞 重组 更重要的是，这些动物提供了一个模型来测试 针对治疗GC介导的免疫缺陷的疗法 在人类身上。 1. Cao，X，Shores，E. W.，et.等人，1995年。 豁免权2：223。 2.伦纳德， W.J.，E.W. Shores，et al. 1995 Immunol. Rev. (in Press）。

Cytokine signals play an essential role in lymphocyte function and development. Disregulation of these signals can impede T cell development and lead to autoimmunity. Recent studies show that individuals possessing mutated cytokine receptor genes exhibit severe immunodeficiency syndromes (XSCID). Many cytokine receptors consist of several chains, some of which are shared between different cytokine receptors. This complexity has made it hard to examine the role of specific cytokines and receptors in different human disease states.The common gamma chain (Gc) is part of the IL-2, IL-4, IL-7, IL-9 and IL-15 receptor complexes. Through its ability to associate with kinases and other molecules, it transduces signals important for lymphocyte function. To examine the role of Gc-mediated signals, mice were generated in which the gene encoding Gc was inactivated by homologous recombination. Examination of these mice demonstrated that lymphocyte development was affected. Although normal populations of T cells, the number of thymocytes was reduced compared to normal thymus. Moreover, we observed an altered CD4/CD8 ratio in the thymus indicating that T cell selection was affected. Peripheral T cells were also affected in Gc-deficient mice. CD8+ cells were consistency low, however, numbers of CD4+ cells increased with age, suggesting a defect in the normal mechanisms of peripheral deletion (apoptosis) of autoreactive cells. While peripheral T cells were functionally unable to respond to TCR engagement, their thymic precursors proliferated in response to TCR engagement. Such findings suggest a role for cytokines in differentially regulating T cell responsiveness vs T cells anergy. B cell development and function was also inhibited. Future experiments will be directed at breeding the Gc-defect into mice expressing transgenes encoding autoreactive antigen receptors. Development of this animal model should be important in understanding the role of cytokines in autoimmune disease and lymphocyte reconstitution. More importantly, these animals provide a model to test therapies directed toward the treatment Gc-mediated immune deficiency in humans. 1. Cao, X, Shores, E.W., et. al. 1995. Immunity 2:223. 2. Leonard, W.J., E.W. Shores, et al. 1995 Immunol. Rev.(in press).