CYCLOSPORINE A: PROMOTER OF LYMPHOMA INDUCTION

拟议研究的主要目的是澄清 淋巴瘤发生的机制 免疫抑制治疗。 环孢素（CsA）目前 临床上使用的最成功的免疫抑制剂之一， 器官移植，但它的使用已被证明与 与淋巴瘤的发展有关 在过去两年中， 支持，我们展示了CsA对 诱导T或B细胞系小鼠淋巴瘤 这取决于给定的引发剂的类型。 我们推测 对促进作用的最合理的解释 CsA干扰胸腺中的T细胞成熟， 刺激淋巴结中的B细胞增殖。 在这 更新应用程序，我们将延长我们的研究在几个 方向 我们将探索复杂的机制 化学致癌物、辐射和逆转录病毒的相互作用 大鼠淋巴瘤模型的建立 莫洛尼鼠白血病病毒诱导的淋巴瘤 与CsA结合作为肿瘤促进剂。 我们将确定 CsA是否对上皮性肿瘤的诱导有影响 采用乌拉坦诱发的小鼠肺腺瘤模型。 我们将进一步确定CsA对T细胞成熟的影响。 使用流式细胞术和T细胞 分化抗原 我们将努力确定 选择的胸腺激素是否可以抵消 胸腺注射环孢素A。 一些细胞的功能 原癌基因与控制细胞凋亡有关， 分化和/或细胞增殖。 我们将调查 选择的细胞原癌基因的转录表达， 胸腺细胞（胸腺）和淋巴细胞（淋巴结）os CsA- 在有或没有启动的情况下处理小鼠，以澄清在多大程度上 原癌基因表达的变化与 胸腺细胞分化和增殖障碍 淋巴细胞 这些研究将提供更好的见解， 只有CsA促进淋巴恶性肿瘤的机制 也包括CsA对免疫系统作用的基本方面。

The major objective of the proposed study is to clarify the mechanism of lymphoma development in patients receiving immunosuppressive treatment. Cyclosporine (CsA) is presently one of the most successful immunosuppressants used in clinical organ transplantation but its use has been shown to be associated with the development of lymphomas. During the past 2 years of support, we demonstrated the promoting action of CsA for the induction of murine lymphoid tumors of either T or B cell lineage depending upon the types of initiating agents given. We postulate that the most plausible explanation for the promoting action of CsA is its interference with T-cell maturation in the thymus and its stimulation of B-cell proliferation in the lymph nodes. In this renewal application we will extend our studies in several directions. We will explore the mechanism underlying complex interactions of chemical carcinogens, radiation and retroviruses in the development of lymphoid tumors by exploiting the rat model of Moloney murine leukemia virus-induced lymphomas in conjunction with CsA as a tumor promoter. We will determine whether CsA has any effects on the induction of epithelial tumors using the model of urethane induced pulmonary adenoma in mice. We will further define the effects of CsA on T-cell maturation in the thymus with the use of a flow cytometry and T-cell differentiation antigens. Attempts will be made to determine whether selected thymic hormones may counteract the effects of CsA on the thymus. Functions of some of the cellular protooncogenes have been implicated to the control of cellular differentiation and/or cell proliferation. We will investigate the transcriptional expression of selected cellular protooncogenes in thymocytes (thymus) and lymphocytes (lymph nodes) os CsA- treated mice with or without initiation, to clarify to what extent changes in protooncogene expression correlate with the disturbance of thymocyte differentiation and proliferation of lymphocytes. These studies will provide better insight into not only the mechanism of CsA-promotion of lymphoid malignancies but also the basic aspects of CsA-action on immune systems.