Antigenic modulation of Friend virus erythroleukemic cells in vitro by serum from mice with dormant erythroleukemia.

Abstract

In the tumor dormant state, small numbers of tumor cells persist in the host without outgrowth to overt neoplasia. The cancer literature contains numerous reports describing recurrence of solid tumors and leukemias years after apparent successful treatment of the primary neoplasia (1). These reports suggest that residual tumor cells can persist in a dormant state during the prolonged clinical remission. Few experimental models have been developed to study the tumor dormant state. In this laboratory we have been investigating a murine model in which the rapidly fatal Friend virus erythroleukemia can be suppressed to a dormant state by treatment with statolon, an extract of mycophage-infected Penicillium stoloniferum cultures (2-4), or the double-stranded RNA extracted from statolon (5). This report describes our continuing analysis of host mechanisms involved in maintenance of Friend leukemia virus (FLV) ~ in a dormant state.Infection of DBA/2 mice with FLV causes a depression in humoral (6) and cellular immunity (7) and macrophage functions (8) followed by the development of a fatal erythroleukemia (2). Treatment of FLV-infected mice with statolon abrogates the depression of humoral immunity and macrophage functions (6,8). Between 50 and 70% of these mice maintain immunocompetence and survive, suppressing the erythroleukemia to a dormant state, which lasts for the normal lifespan of most of these mice (2-4, 9). However, late in life, some of these mice develop erythroleukemia from which FLV can be isolated (2, 3). Mice with dormant FLV infections contain antibodies that complex FLV virion polypeptides and are cytotoxic for FLV-transformed cells, and these antibodies appear to be crucial for leukemosuppression and maintenance of the virus in a dormant state (9-11). Serum from mice with dormant l%V infections is referred to as dormant FLV-immune serum (FVIS).The precise mechanism by which FLV antibodies suppress FLV erythroleukemia and maintain the virus in a dormant state is not known. DBA/2 mice are deficient in the fifth component of complement (C5) (12) which is required for antibody-mediated complementdependent immune cytolysis (13). Carlson and Terres demonstrated antibody-dependent killing of syngeneic lymphomas by the DBA/2 mouse in vivo (14). The mechanism involved in this destruction of the lymphomas was most likely antibody-dependent cell-* Supported by National Institutes of Health grant no. 5 R01 CA12461. 1Abbreviations used in this paper: ADCC, antibody-dependent cell-mediated cytotoxicity; EBV, Epstein-Barr virus; FLC-745 cells, clone 745 of Friend erythroleukemia cells; fl-GAMg, fluorescein-conjugated goat anti-mouse 7S gamma globulin; FLV, Friend leukemia virus; FVIS, immune serum from mice with dormant Friend virus infection; GCSA, Gross virus cell surface antigen; MuMTV, murine mammary tumor virus; NMS, normal mouse serum; PBS, phosphatebuffered saline; TL, thymus-leukemia.

Persistence and pathogenicity of defective Friend spleen focus-forming virus. Decreased transplantability of hemopoietic cells as a marker for preleukemic change.

“…We have not been able to detect virus neutralizing antibodies in SFFV ÷ preleukemic mice, but this does not preclude the possibility of rapid development of humoral immunity to MuLV infection. It has been shown that the induction of FV cytotoxic antibodies may be a contributing mechanism in the development of dormant FV infection (33,34) and in the regression of FV disease (35). An important alternative explanation is based upon our previous observation that SFFV may be classified as a DI particle (9).…”

Friend Erythroleukaemia Cell Mutants Defective in Viral Gene Expression

“…1. As FR-6 was stably resistant to the antibody for more than 6 months, the clone could be a true mutant, but many other cells in the population which resisted the antibody after immunoselection could have been the ones whose target molecules were simply masked in the presence of antibody as in antigenic modulation of FLC-745 cells (Genovesi et al, 1977) or TL cells (Old et al, 1968). We recently observed that the virus non-producers obtained above formed large aggregates spontaneously when mixed with virus-producing parental cells and the virus producers in such aggregates appeared to resist complement-dependent cytotoxicity.…”

In vitro growth inhibition of murine leukemia cells by antibody specific for the major envelope glycoprotein (gp71) of friend leukemia virus

“…under conditions of growth inhibition While modulation of FLV gp71 expression on leukemia cells exposed to appropriate antisera without C' in vitro or in vivo has been described in the absence of any significant effects on cell replication and/or growth (Genovesi et al, 1977;Callahan et al, 1980;Stackpole et al, 19801, in a n attempt to elucidate the mechanism of the antibody-mediated growth inhibition described above it was decided to determine whether antigenic modulation occurs under these conditions. FLC-745 cells were cultured in inhibitory medium containing 185 pglml of GaFLV gp71 IgG or control medium containing 225 pg/ ml of NGS IgG, and viable cells from each culture were tested for susceptibility to lysis by exogenous C' alone or by fresh AGaFLV gp71 serum + C'.…”