DIFFERENTIAL EFFECT OF CYCLOSPORINE ON LYMPHOCYTE SUBSET

环孢菌素（CSA），凭借其免疫抑制作用， 无骨髓毒性，大大提高了 器官移植 尽管其广泛的临床应用， 然而，CSA发挥其选择性作用的确切机制 免疫抑制没有详细描述。 最初认为 CSA的大部分效应可以通过其抑制 白细胞介素2（IL 2）分泌。 最近的研究表明， 这是CSA的唯一影响 特别是，CSA 似乎抑制IL 2反应性（如通过 增殖）;这种抑制似乎更为深刻 没有严格的相关性， IL 2受体（IL 2 R）的表达。 然而，大多数研究 使用未分级的淋巴细胞群进行。 我们 假设CSA可能或可能不抑制IL 2反应性 这取决于检查的淋巴细胞亚群。 的机制 将研究这种差异抑制作用。 最近的动物模型证据表明， 体内施用的CSA的免疫抑制特性可以 取决于是否有完整的胸腺 这种可能性 很少受到关注。 这项提案将考验 CSA对胸腺细胞有显著影响假说 亚群和胸腺上皮。 这一假设将得到检验 无论是在体内还是体外。 一旦文件化，CSA的作用- 诱导胸腺改变的耐受性的发展， 移植器官和诱导自身反应性克隆将 被解决。

Cyclosporine (CSA), by virtue of its immunosuppressive action and lack of myelotoxicity, has greatly improved the rate of success of organ transplantation. Despite its widespread clinical use, however, the exact mechanism by which CSA exerts its selective immunosuppression is not well detailed. It was initially thought that most of CSA effects can be explained by its inhibition of interleukin 2 (IL2) secretion. Recent studies have cast doubt about this being the sole effect of CSA. In particular, CSA appears to inhibit IL2 responsiveness (as determined by proliferation); this inhibition appears to be far more profound than, and does not have stringent correlation with, the inhibition of IL2 receptor (IL2R) expression. However, most of these studies were done utilizing unfractionated lymphocyte populations. We hypothesize that CSA may or may not inhibit IL2 responisveness depending on the lymphocyte subset examined. The mechanisms for such differential inhibitory action will be studied. Recent evidence in animal models suggests that some of the immunosuppressive properties of CSA administered in vivo may be dependent on the presence of an intact thymus. This possibility has received little attention. This proposal will test the hypothesis that CSA exerts significant effects on thymocyte subsets and the thymic epithelium. This hypothesis will be tested both in vivo and in vitro. Once documented, the role of CSA- induced thymic alterations in the development of tolerance to the transplanted organ and in the induction of autoreactive clones will be addressed.