CYCLOSPORINE A: PROMOTER OF LYMPHOMA INDUCTION

拟议研究的主要目的是澄清 非霍奇金淋巴瘤患者的发病机制 免疫抑制治疗。环孢素(CsA)目前是 临床应用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 随着淋巴瘤的发展。在过去的两年中 支持，我们展示了CSA对 T和B细胞系小鼠淋巴样肿瘤的诱导 取决于所给引发剂的类型。我们假设 最合理的解释就是 CsA是干扰胸腺T细胞成熟和 它能刺激B细胞在淋巴结中的增殖。在这 续期申请我们将在几个方面延长我们的学习 方向。我们将探索复杂性背后的机制 化学致癌物、辐射和逆转录病毒的相互作用 大鼠淋巴样肿瘤动物模型的建立 莫洛尼小鼠白血病病毒诱导的淋巴瘤 与环孢素A联合作为肿瘤促进剂。我们将决定 环孢素A对上皮性肿瘤的诱导作用 采用乌拉坦诱导的小鼠肺腺瘤模型。 我们将进一步确定CsA对T细胞成熟的影响。 用流式细胞仪和T细胞检测胸腺 分化抗原。将尝试确定 选定的胸腺激素是否可以中和 胸腺上的环孢素A。一些细胞的功能 原癌基因已被认为与控制细胞 分化和/或细胞增殖。我们将调查 部分细胞原癌基因的转录表达 胸腺细胞(胸腺)和淋巴细胞(淋巴结节) 用或不用启动的方法处理小鼠，以明确在多大程度上 原癌基因表达的变化与 小鼠胸腺细胞分化和增殖障碍 淋巴细胞。这些研究将为NOT提供更好的洞察 只有CsA促进淋巴系统恶性肿瘤的机制 而且还有CsA的基本方面--对免疫系统的作用。

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.