ROLE OF A-INTERFERON RECEPTOR IN HUMAN IMMUNOREGULATION

该提案的目的是在分子上定义， 功能水平的机制，α-干扰素（IFN） 调节人体免疫反应，包括抗体 生产，在体外。 干扰素受体表达分析 将主要用作探针，以检查 IFN在质膜和亚细胞水平上， 确定其他淋巴因子的作用，已知影响 抗体形成，对IFN受体表达的影响。 在这 因此，我们建议：（1）确定 α-IFN和/或α-IFN受体是介导细胞凋亡所必需的。 观察到对抗体产生的影响，2）表征 特异性结合位点的亚细胞器定位 α-IFN，3）监测IFN和/或IFN α的细胞内运输 受体复合物，4）关联α-IFN受体表达 与细胞周期，和5）确定可能的细胞来源， 内源性α-干扰素参与的生理调节 人抗体生产。 两个主要方法将是 为了解决这些基本问题：a）无线电- 碘化重组α-干扰素将用于确定 特异性α-干扰素受体的亚细胞定位， 监测干扰素通过细胞内 和B）单克隆抗体的产生 特异于α-干扰素受体，如本申请中所提出的， 研究，将明确促进阿尔法的作用的调查- IFN受体介导的生物学效应。 初步研究将 使用IFN-敏感和抗性细胞系进行， 每个细胞表达非生理数量的受体。 最终，IFN受体表达与 生物功能的调节（即，抗体生产）将 依赖于使用从正常人获得的人淋巴细胞， 捐助者。 最近，α-IFN已被证明是 有效治疗多种淋巴源性 恶性肿瘤，包括毛细胞白血病、急性淋巴细胞白血病 白血病和多发性骨髓瘤。 已经假定 已证实的抗肿瘤作用可能涉及免疫调节 肿瘤细胞群的数量。 因此，研究调查的基本 IFN参与免疫调节的机制应清楚 深入了解IFN与恶性细胞的相互作用 对干扰素敏感和抵抗的患者。

The purpose of this proposal is to define on a molecular and functional level the mechanisms by which alpha-interferon (IFN) modulates human immune responses, including antibody production, in vitro. Analysis of interferon-receptor expression will be used primarily as a probe to examine the interaction of IFN at both the plasma membrane and subcellular level and to determine the effect of other lymphokines, known to effect antibody formation, on the expression of IFN receptors. In this regard, we are proposing to 1) determine if internalization of alpha-IFN and/or alpha-IFN receptor is required to mediate the observed effect on antibody production, 2) characterize subcellular organelle localization of specific binding sites for alpha-IFN, 3) monitor intracellular trafficking of IFN and/or IFN receptor complexes, 4) correlate alpha-IFN receptor expression with cell cycle, and 5) determine possible cellular sources of endogenous alpha-IFN involved in the physiologic regulation of human antibody production. Two major approaches will be utilized to address these fundamental questions: a) radio- iodinated-recombinant alpha-interferon will be used to determine subcellular localization of specific alpha-interferon receptors and to monitor trafficking of interferon through intracellular compartments, and b) the production of monoclonal antibodies specific for the alpha-interferon receptor, as proposed in this study, will clearly facilitate the investigation of the role of alpha- IFN receptor in mediating biological effects. Initial studies will be carried out using IFN-sensitive and resistant cell lines which express non-physiologic numbers of receptors per cell. Ultimately, correlation between IFN receptor expression and modulation of biologic function (i.e., antibody production) will depend on the use of human lymphocytes obtained from normal donors. Recently, alpha-IFN has been demonstrated to be effective in the treatment of several lymphoid derived malignancies including hairy cell leukemia, acute lymphoblastic leukemia and multiple myeloma. It has been postulated that demonstrated anti-tumor effects may involve immunomodulation of the tumor cell population. Thus, studies investigating the basic mechanisms of IFN involved in immunoregulation should clearly provide insight into the interaction of IFN with malignant cells from both IFN-sensitive and resistant patients.