The purpose of this proposal is to define on a molecular, cellular and functional level the mechanisms by which the interferons (IFN) modulate human antibody production in vitro and to test the hypothesis that they may function as immunoregulatory or differentiation-inducing lymphokines in controlling the proliferation of certain B cell malignancies such as nodular lymphoma and hairy cell leukemia. The objectives are: 1) to characterize cellular receptors for interferon expressed by human peripheral blood lymphocyte subsets and malignant cells, 2) to examine the effects of the interferons on phenotypically and functionally define human T cell subsets and 3) to examine the effects of IFN in inducing phenotypic and functional differentiation in vitro of both defined B leukemia/lymphoma cell lines and B malignant populations from patients with nodular lymphoma and hairy cell leukemia. Detection of binding of radioiodinated interferons to human lymphocytes will be used as a probe in the following specific aims: 1) to determine subcellular organelle localization of specific cellular binding sites for the interferons, 2) to monitor cellular uptake of interferon receptors analogous to peptide-hormone receptor mechanisms, 3) to directly determine if the interferons exert their biological functions, including augmentation of antibody production and NK activity in vitro, via receptor mechanisms, and 4) to examine the interrelationship of other lymphokines and interferon receptor expression. From the standpoint of immunoregulation of T cell functions by the interferons, the specific aims are: 1) to examine the effects of the interferons on suppressor and helper T-cell function, defined in a model system involving human primary and polyclonal antibody production in vitro, 2) to study the effect of interferon on phenotypic T cell differentiation, 3) to investigate possible modulation by the interferons of T cell expression of interleukin-2 receptors, and 4) to assess the effects of other lymphokines on interferon-enhanced antibody production in vitro. Finally, the in vitro mechanisms by which IFN (and other lymphokines) might promote differentiation of B cell neoplasms via receptor interactions with normal and/or malignant cellular subsets will be investigated. These studies are thus designed to enhance understanding of the mechanisms involved in interferon modulation of human immune responses and tumor growth in vivo and in vitro.
