DIFFERENTIAL EFFECT OF CYCLOSPORINE ON LYMPHOCYTE SUBSET

免疫系统的标志是它能够区分“自我”和“免疫系统”。 “非自我”;不这样做可能会导致自身免疫性疾病。 教育 免疫系统的自我概念发生在胸腺 其中自身反应性淋巴细胞被缺失、耐受化或主动 抑制 克隆缺失是一种主要的，尽管不是唯一的， 自我宽容 克隆缺失发生的确切过程是 尽管有几种自身免疫动物模型， 这种疾病可以通过过继转移正常的 胸腺细胞 这表明胸腺细胞亚群可能参与了 克隆缺失 首席研究员最近发现了一个 新的鼠胸腺细胞亚群（NK 1.1+，CD 3+，CD 4-，CD 8-，CD 5+，CD 44+， Thy 1+，TCR α/β），其具有自发裂解潜力。 后 用白细胞介素2（IL 2）扩增，这个群体可以杀死新鲜的 自体CD 4+、CD 8+胸腺细胞以及PHA激活的成熟 胸腺细胞 这些属性是假设NK1.1+， CD 3+胸腺细胞在胸腺细胞克隆缺失方面是重要的。 选择. 该假设将利用体内和体内试验进行检验。 体外策略 主要重点将放在审查的影响， 新生儿环孢素（CSA）管理，导致发展 自身免疫性疾病，对这些胸腺细胞的功能和数量的影响。 程序性细胞死亡是另一种自我耐受的方法。 被认为是完成。 抗CD 3在体内诱导小鼠细胞凋亡 胸腺细胞 初步数据显示，除了细胞凋亡，抗- CD 3导致CD 4+、CD 8+胸腺细胞几乎完全耗尽，同时伴随着CD 4+、CD 8+胸腺细胞的减少。 NK1.1+、CD 3+亚群的扩增和细胞毒性T细胞的激增， 效应细胞; CSA似乎消除了所有这些变化。 假设， 体内抗CD 3的胸腺效应是介导的， 在很大程度上，通过精氨酸诱导的NK1.1+的活化和扩增， CD 3+胸腺细胞。 体内T细胞耗竭已经在临床上用于某些 自身免疫性疾病和治疗器官移植排斥。 有 很少有人知道这种治疗对免疫系统的影响， 整个，其互动反馈机制，并没有注意到， 给予胸腺。 这一建议有望取得丰硕成果 临床应用于自身免疫和移植领域。

The hallmark of the immune system is its ability to distinguish "self" from "non-self"; failure to do so may result in autoimmune disease. Education of the immune system as to the concept of self takes place in the thymus wherein autoreactive lymphocytes are deleted, tolerized or actively suppressed. Clonal deletion is a major, albeit not the only, mechanism for self tolerance. The exact process by which clonal deletion takes place is not well understood although there are several autoimmune animal models in which the disease can be ameliorated by the adoptive transfer of normal thymocytes. This suggests that a thymocyte subset(s) may be involved in clonal deletion. The principal investigator has recently identified a novel murine thymocyte subset (NK1.1+, CD3+, CD4-, CD8-, CD5+, CD44+, Thy1+, TCR alpha/beta) which has a spontaneous lytic potential. Upon expansion with interleukin 2 (IL2), this population could kill fresh autologous CD4+, CD8+ thymocytes as well as PHA-activated mature thymocytes. These attributes are the basis of the hypothesis that NK1.1+, CD3+ thymocytes are important in the clonal deletion aspect of thymic selection. This hypothesis will be tested utilizing an in vivo and in vitro strategy. Major emphasis will be placed on examining the effect of neonatal cyclosporine (CSA) administration, which leads to the development of autoimmune disease, on the function and number of these thymocytes. Programmed cell death is another method by which self-tolerization is thought to be accomplished. Anti-CD3, in vivo, induces apoptosis in murine thymocytes. Preliminary data showed that, in addition to apoptosis, anti- CD3 causes near total depletion of CD4+, CD8+ thymocytes with a concomitant expansion of the NK1.1+, CD3+ subset and an insurgence of cytotoxic effector cells; CSA seems to abolish all these changes. The hypothesis to be tested is that the thymic effects of in vivo anti-CD3 are mediated, to a large extent, by cytokine-induced activation and expansion of NK1.1+, CD3+ thymocytes. T cell depletion, in vivo, is already being used clinically in certain autoimmune diseases and in treating organ transplant rejection. There is little known about the effects of such treatment on the immune system as a whole, with its interactive feedback mechanisms, and no attention has been given to the thymus. This proposal is expected to yield fruitful results clinically applicable in the autoimmunity and transplantation areas.