Natural human antibodies to gamma interferon interfere with the immunomodulating activity of the lymphokine.

Abstract

Natural antibodies to y interferon (IFN-y) were found in patients suffering from different viral diae and, at a lower titer, in healthy individuals. Such antibodies were affinity-purified and studied for their capability to interfere in vitro with the antiviral and immunomodulating activity of IFN-y. Data obtained show that these human anti-IFN-y antibodies have no inhibitory effect on the antiviral activity of IFN-y. On the contrary, they are able to inhibit the expression of Fc receptor sites and HLA-DR antigens induced by IFN-y on the U-937 cells, a human monocytoid/macrophage-derived cell line. These antibodies can also interfere in a mixed lymphocyte culture (MLC) with the proliferation of lymphocytes and the generation of cytotoxic lymphocytes. However, they showed only a moderate inhibitory effect on the cytotoxicity generated in MLC to K-562 cells. Human antibodies capable of interfering with the immunomodulating activities of IFN-y might open up a new field in clinical therapy for those diseases that carry evidence of activated cell-mediated immunity.Interferons (IFNs) form a heterogeneous family of proteins that are defined according to their ability to prevent viral replication (1). So far, three major classes of human IFN have been identified: a, ,3, and y interferons (IFN-a, IFN-P, and IFN-'y). IFN-y shares several characteristics and activities with IFN-a and IFN-,l, but it also mediates various immune functions (2, 3).As self-recognized substances, human IFNs should not elicit antibodies in man, except in conjunction with autoimmune disorders (4) or in patients receiving large amounts of exogenous IFN, administered parenterally over a long period of time (5-7). However, there is no valid explanation for the observed presence of spontaneous anti-IFN-a antibodies in a small number of patients with cancer (8); for the presence of IFN-y antibodies in HIV-infected patients (9), in individuals suffering from various viral diseases, and even (at low titer) in healthy individuals (10); or for the presence of antibodies to all three species of IFN in healthy donors (11,12). The specific increase observed in the anti-IFN-'y antibody titer during viral infection and its decrease following resolution of the disease indicate that these antibodies are related to viral infection, possibly as a consequence of the production of IFN-y after antigenic stimulation in vivo (10).This paper explores the ability of affinity-purified natural human IFN-y antibodies to affect the antiviral and immunomodulating activity of the human lymphokine in vitro. Our results show that affinity-purified human anti-IFN-y antibodies do not impair the antiviral activity of IFN-'y, although they are capable of suppressing the IFN-y induction of class II major histocompatibility complex (MHC) antigens and of Fc receptor sites for immunoglobulin. We also found that natural anti-IFN-y antibodies can interfere, in a mixed lymphocyte culture (MLC), with the proliferation and cytotoxic generation of lymphocytes, probably by inhibitin...

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