ROLE OF A-INTERFERON RECEPTOR IN HUMAN IMMUNOREGULATION

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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.