DIFFERENTIAL EFFECT OF CYCLOSPORINE ON LYMPHOCYTE SUBSET

免疫系统的特点是它能区分“自我”和“自我” “非我”；不这样做可能会导致自身免疫性疾病。教育 免疫系统关于自我概念的研究发生在胸腺 其中自身反应性淋巴细胞被删除、耐受或活跃 被压制了。克隆删除是一种主要的，尽管不是唯一的机制 自我宽容。进行克隆删除的确切过程是 虽然有几种自身免疫的动物模型，但还不是很清楚 通过对正常人的收养转移可以改善哪些疾病 胸腺细胞。这表明胸腺细胞亚群(S)可能参与了 克隆性删除。首席调查员最近发现了一种 新的小鼠胸腺细胞亚群(NK1.1+，CD3+，CD4-，CD8-，CD5+，CD44+， Thy1+，TCRα/β)，其具有自发裂解电位。vt.在.的基础上 在白介素2(IL2)的作用下，这个种群可能会杀死新鲜的 自体CD_4~+、CD_8~+胸腺细胞及PHA激活的成熟细胞 胸腺细胞。这些属性是假设NK1.1+的基础， CD3+胸腺细胞在胸腺克隆缺失方面很重要 选择。这一假说将通过体内和体内的 体外策略。主要的重点将放在审查的影响 新生儿环孢素(CsA)的应用 自身免疫性疾病对这些胸腺细胞的功能和数量的影响。 程序性细胞死亡是自我耐受的另一种方式 被认为是完成的。抗CD3抗体在体内诱导小鼠细胞凋亡 胸腺细胞。初步数据显示，除细胞凋亡外，抗肿瘤药物 CD3导致CD4+，CD8+胸腺细胞几乎完全耗尽 NK1.1+、CD3+亚群的扩增和细胞毒作用的爆发 效应细胞；CsA似乎可以消除所有这些变化。假设是为了 有待检验的是，体内抗CD3抗体的胸腺效应是由 在很大程度上，通过细胞因子诱导的NK1.1+的激活和扩张， CD3+胸腺细胞。 在活体内，T细胞耗尽已经在某些临床上使用 自身免疫性疾病和器官移植排斥反应的治疗。的确有 鲜为人知的是这种治疗对免疫系统的影响 整体上，以及它的互动反馈机制，一直没有引起注意 给胸腺的。这项建议可望产生丰硕的成果 临床适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.