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Showing papers on "Friend leukemia published in 1986"


Journal ArticleDOI
07 Nov 1986-Science
TL;DR: Mice inoculated with live recombinant vaccinia virus had an envelope-specific T-cell proliferative response and, after challenge with Friend virus complex, developed neutralizing antibody and cytotoxic T cells (CTL) and were protected against leukemia.
Abstract: The current prevalence of the acquired immune deficiency syndrome in humans has provoked renewed interest in methods of protective immunization against retrovirus-induced diseases. In this study, a vaccinia-retrovirus recombinant vector was constructed to study mechanisms of immune protection against Friend virus leukemia in mice. The envelope (env) gene from Friend murine leukemia virus (F-MuLV) was inserted into the genome of a vaccinia virus expression vector. Infected cells synthesized gp85, the glycosylated primary product of the env gene. Processing to gp70 and p15E, and cell surface localization, were similar to that occurring in cells infected with F-MuLV. Mice inoculated with live recombinant vaccinia virus had an envelope-specific T-cell proliferative response and, after challenge with Friend virus complex, developed neutralizing antibody and cytotoxic T cells (CTL) and were protected against leukemia. In contrast, unimmunized and control groups developed a delayed neutralizing antibody response, but no detectable CTL, and succumbed to leukemia. Genes of the major histocompatibility complex influenced protection induced by the vaccinia recombinant but not that induced by attenuated N-tropic Friend virus.

142 citations


Journal Article
TL;DR: The results indicated that a major contribution to the relative susceptibility and resistance of the host to FLV was controlled by the capacity to mobilize T-cells to the spleen in an early stage of disease, although the interaction of these T- cells with other immune cells may play an important role in mediating host resistance toFLV-induced disease.
Abstract: The in vivo roles of the immunosurveillance mechanism of the host against leukemia induced by Friend leukemia virus (FLV) were examined. The significance of T-cells in host defense against FLV-induced leukemia was indicated by the fact that thymus-deprived C57BL/6N- nu/nu mice were sensitive to FLV, although normal C57BL/6N mice were, as already reported by many authors, resistant to FLV. In relation to the role of T-cells on the onset of FLV-induced leukemia, the population dynamics of the lymphocytic subpopulations of the systemic lymphoid organs after FLV injection in FLV-resistant C57BL/6N mice were examined in comparison with the dynamics in FLV-sensitive strains, C57BL/6N- nu/nu mice and normal C3H/HeN mice. In this system, Lyt-1+2- helper T-cells in the spleen of FLV-resistant C57BL/6N mice increased in number after FLV injection. The number of immunoglobulin positive cells did not remarkably change in FLV-resistant C57BL/6N mice after FLV injection, whereas the number increased in the lymph node of FLV-sensitive C3H/HeN mice. The results indicated that a major contribution to the relative susceptibility and resistance of the host to FLV was controlled by the capacity to mobilize T-cells to the spleen in an early stage of disease, although the interaction of these T-cells with other immune cells may play an important role in mediating host resistance to FLV-induced disease.

29 citations


Journal ArticleDOI
TL;DR: Serological examination indicated that immunity against death from leukaemia was mediated by specific antibodies, predominantly induced by immunization with the gp70 env gene product, since p15E showed only minor protection.
Abstract: Summary Vaccines prepared from Friend leukaemia virus envelope and core polypeptides were compared for their efficiency in preventing erythroleukaemia in mice. High doses (100 µg) of gp85, the micellar complex of the envelope polypeptides gp70 and p15E, completely protected STU mice. The same dose of purified gp70 still protected about 80% of the animals, while p15E did not affect the cumulative mortality. The internal viral polypeptide p30 was ineffective. Serological examination indicated that immunity against death from leukaemia was mediated by specific antibodies. These leukaemia-preventing antibodies were predominantly induced by immunization with the gp70 env gene product, since p15E showed only minor protection. Glycoprotein gp70, however, was more effective when given as the gp85 micellar complex. An even more potent vaccine was obtained when gp70 was coupled to keyhole limpet haemocyanin (KLH) by glutaraldehyde. Ten µg gp70 coupled to KLH was enough to save more than 90% of Friend leukaemia virus-infected mice from erythroleukaemia. KLH may also be a suitable experimental carrier for subunits of gp70 or synthetic oligopeptides for viral vaccines.

20 citations


Journal ArticleDOI
TL;DR: 5-Aza-β-lactam compounds showed differentiation-inducing-activity toward all of three types of Friend leukemia cells, two of which were dimethylsulfoxide (DMSO)-sensitive and the other of which was DMSO-resistant.
Abstract: β-, γ-, δ- and aza-β-lactam, and thiaziadine compounds induced the differentiation of Friend leukemia cells and hemoglobin was produced. Modification of the lactam rings of γ- and (δ-lactam compounds with aromatic side chains and bromine atoms enhanced their differentiation-inducing-activities to Friend leukemia cells. On the other hand, 4 thiaziadine compounds (AKT-1, AKT-2, AKT-3 and AKT-4), which commonly contain a -N(CH3)-N(CH3)-moiety, also promoted the differentiation of Friend leukemia cells. They had specific differentiation-inducing-abilities without toxic effects to Friend leukemia cells. 5-Aza-β-lactam compounds showed differentiation-inducing-activity toward all of three types of Friend leukemia cells, two of which were dimethylsulfoxide (DMSO)-sensitive and the other of which was DMSO-resistant. But we did not find any correlation between the differentiation-inducing-activity and the chemical group at the 1-imino position. The presence of an amino bond, which commonly exist in differentiation...

16 citations


Journal ArticleDOI
TL;DR: The available data support the tentative classification of gamma-FA as a murine differentiation antigen as a function of growth state (blast or dimethyl sulfoxide-differentiated) and cell-cycle compartment.
Abstract: Quantitative analysis of extracts of various normal adult CD-1 mouse tissues indicated that the serologically defined murine gamma fetal antigen (gamma-FA) was expressed at high levels in hematopoietic tissue in general and in bone marrow (BM) in particular. Metabolic labeling of isolated BM cells indicated that the BM was a site of gamma-FA synthesis in the adult animal. The size(s) of the antigen immunoprecipitated from labeled BM cells (35 and 27 kilodaltons) with anti-gamma-FA serum correlated well with molecular weight estimates of fibrosarcoma-fetal mouse-associated gamma-FA, as determined by molecular sieve chromatography. For ascertainment of the relationship between hematopoietic cell differentiation and gamma-FA content, a multiparameter flow cytometric approach was used to evaluate gamma-FA levels in Friend erythroleukemia (FL) cells as a function of growth state (blast or dimethyl sulfoxide-differentiated) and cell-cycle compartment. Differentiated G1-arrested FL cells (G1D) possessed significantly lower gamma-FA-associated immunofluorescence as compared to control cells in the G0-G1 substate. Remaining S- and G2 + M-phase cells in differentiated populations demonstrated an even greater reduction in gamma-FA content relative to control cells in the corresponding cell-cycle phases. The available data support the tentative classification of gamma-FA as a murine differentiation antigen.

13 citations


Journal ArticleDOI
TL;DR: The presence of vaccinia virus DNA sequences in the nucleus apparently did not affect the size of the provirus, the integration pattern or the expression of the leukemia virus.

10 citations


Journal Article
TL;DR: The ability of macrophages to induce leukemia regression correlates with nonimmunological, in vivo suppression of normal and susceptible leukemic erythroid progenitors and is suggested to be due to changes in a humoral regulator, related to but independent of erythropoietin.
Abstract: The acute erythroleukemia induced in mice by the anemia-inducing strain of the Friend virus complex is caused to regress by normal macrophages. We examined the possibility that reversal of leukemia is related to a macrophage regulatory function in erythropoiesis. We found that the ability of macrophages to induce leukemia regression correlates with nonimmunological, in vivo suppression of normal and susceptible leukemic erythroid progenitors. The macrophage effect on erythropoiesis appears to be due to changes in a humoral regulator, related to but independent of erythropoietin. The results suggest a novel regulatory system for erythropoiesis, operative in vivo, and involving macrophages as accessory or suppressor cells. This regulation appears to be disrupted in erythroleukemic mice, but can be restored, and the disease can be made to regress by treatment with normal macrophages.

8 citations


Journal Article
TL;DR: In this paper, a passive transfer of sensitized T-cells from regressing FV immunized or regressed mice caused regression of the conventional lethal leukemia induced by FV. This model thus provides an experimental system of highly effective passive cellular immunotherapy against an autochthonous, fully developed leukemia.
Abstract: The erythroleukemia induced in susceptible mice by Friend virus (FV) is a progressive, lethal disease. A variant strain of Friend virus (regressing FV) produces a histopathologically identical leukemia except that the disease spontaneously regresses in 50% of leukemic mice. Normal T-cell and macrophage function are required for regression to occur and in animals that are going to regress, specifically reactive T-cells are found in the spleen. Passive transfer of sensitized T-cells from regressing FV immunized or regressed mice caused regression of the conventional lethal leukemia induced by FV. To expand the effector cell populations, characterize them and improve their therapeutic efficacy, sensitized T-cells were cultured in vitro . The T-cells, isolated from regressed or immunized mice, were grown and expanded in vitro with interleukin 2 and antigen (mitomycin C treated regressing FV-infected cell lines). The T-cells demonstrated high levels of in vitro cytotoxicity against FV antigens but exhibited no blastogenic response to the same antigens. When fully FV-induced leukemic mice (14 days post virus inoculation; spleen weight, >0.75 g) were given one injection of 5 × 106 in vitro cultured T-cells and no other treatment the mice experienced permanent regressions of their disease. From T-cell cultures depleted of specific cell populations with monoclonal antisera, helper Lyt-1+ cells were shown to be responsible for permanent regressions (cures), whereas cytotoxic Lyt-2+ cells caused temporary leukemia remissions. This model thus provides an experimental system of highly effective passive cellular immunotherapy against an autochthonous, fully developed leukemia, requiring no adjunctive treatment for activity.

7 citations


Journal ArticleDOI
TL;DR: Findings showed that time and dosage were critical to the protective effect of tuftsin against virus-induced leukaemia against FLV infection.
Abstract: Summary A significant decrease in mortality was observed when 25 µg of the tetrapeptide tuftsin was given to DBA/2J mice 5 days before infection with Friend leukaemia virus (FLV). The same effect was observed when tuftsin was given 5 days before and twice a week for 3 weeks after FLV infection. No effect was observed when the same amount of tuftsin was given 1 day before infection. A 5 µg dose of tuftsin given 5 days before and twice-weekly for 3 weeks had no effect on leukaemia induced by FLV infection. These findings showed that time and dosage were critical to the protective effect of tuftsin against virus-induced leukaemia.

6 citations


Journal ArticleDOI
TL;DR: The data suggest that the "low" in vivo tumorigenicity of in vitro passaged FLC is, at least in part, due to host's NR directed against target structures associated with leukemia cells.

6 citations


Journal Article
TL;DR: It is reported that milk-transmitted MuMTV also delays the development of the acute erythroleukemia induced by Friend leukemia virus (FLV), and retards, or prevents in some cases, theDevelopment of long-term lymphomas caused by its helper component.
Abstract: We have previously shown that mice simultaneously infected with the murine mammary tumor virus (MuMTV) and with certain slow murine leukemia viruses (MLV) have an increased resistance to the pathological effects of both agents. Here we report that milk-transmitted MuMTV also delays the development of the acute erythroleukemia induced by Friend leukemia virus (FLV), and retards, or prevents in some cases, the development of long-term lymphomas caused by its helper component. This is confirmed by the observation that the average life span of MuMTV-carrying mice infected with FLV or its helper component is prolonged by over 30% as compared to that of MuMTV-free animals infected with the same agents and by the finding that the replication of Friend viruses is reduced in mice neonatally exposed to MuMTV. Since the antibody responses of mice to MuMTV and to FLV were not cross-reactive, we searched for antiviral activity in the tissues of mice exposed to MuMTV, FLV, or the helper component of FLV. Low levels of interferon-α/-β were consistently detected in spleen extracts from mice infected with all these agents but could not be demonstrated in the spleens of uninfected BALB/c mice; thus, the chronic production of endogenous interferon is likely to play a major role in the reciprocal interference in vivo between retroviruses belonging to different genera.

Journal ArticleDOI
TL;DR: When adriamycin-sensitive and resistant Friend leukemia cells were exposed to cytotoxic concentrations, the pulverization phenomenon was not observed and 75-80% of cells were without breaks, suggesting a different mechanism for cytotoxicity in sensitive and resistant cells.

Journal ArticleDOI
TL;DR: Several kinds of anthracyclines having γ-rhodofnycinone as the aglycone were isolated from Streptomyces cosmosus TMF 518, and their derivatives were prepared by chemical modification to clarify their structure activity relationship.
Abstract: Several kinds of anthracyclines having γ-rhodofnycinone as the aglycone were isolated from Streptomyces cosmosus TMF 518, and their derivatives were prepared by chemical modification. We tested their differentiation inducing activity in Friend leukemia cells and clarified their structure activity relationship as follows: 1) The aglycone, γ-rhodomycinone, had no differentiation inducing activity but was cytotoxic; 2) the compounds with two sugar chains at both C7 and C10 had more potent differentiation inducing activity than those with only a sugar chain at C-10; 3) cosmomycin C was the most favorable candidate for an anticancer agent of all anthracyclines tested, because the value of ED50 (cytotoxicity)/ED50 (differentiation) was as high as 3000; and 4) the increase in differentiation inducing activity and cytotoxicity was not always in parallel.

Journal ArticleDOI
30 Apr 1986-Virology
TL;DR: Results indicate that F-MuLV expression does not result per se in a high immunogenic potential of tumor cells, and it is tempting to speculate that the selection of virus nonproducer cell variants after in vivo passages of interferon-sensitive 745 cells could depend on the presence of low levels of endogenous interferons in normal young mice.

Book ChapterDOI
01 Jan 1986
TL;DR: Genetically susceptible mice inoculated with the entire FLC develop a rapidly progressing erythroblastosis of the spleen followed by erythroleukemia within a few weeks postinfection—a series of changes thought to be initiated by the rapidly transforming replication-defective spleen focus-forming virus.
Abstract: Exogenous retroviruses are the cause of severe immunodeficiency syndromes in humans and animals (4). Studies in our laboratory have focused on elucidating the mechanisms underlying the immunodeficiency induced in mice by retroviruses of the Friend leukemia complex (FLC). The pathologies produced by the two viral components of this complex are considerably different. Genetically susceptible mice inoculated with the entire FLC develop a rapidly progressing erythroblastosis of the spleen followed by erythroleukemia within a few weeks postinfection—a series of changes thought to be initiated by the rapidly transforming replication-defective spleen focus-forming virus. In contrast, the slow transforming replication-competent helper virus (F-MuLV), when injected alone into the same strains of mice, causes leukemias of varied histotype after a latency of several months, the only change noticeable during the long incubation period being a slight hyperplasia of the spleen (11,32).

Journal ArticleDOI
TL;DR: The present results suggest that the sensitivity to the synergistic cytotoxic effect of IFN and TNF in these cells is correlated with the ability to be induced into an antiviral state.
Abstract: Interferon-α/β (IFN-α/β)-sensitive (FLC 745) and -resistant (FLC 3C18) Friend leukemia cells (FLC) were fairly refractory to the cytotoxicity of murine tumor necrosis factor (MuTNF) in vitro. Both lines became highly sensitive to mTNF when treated in combination with murine IFN-γ; when treated with IFN-α/β, only the FLC 745 became sensitive to MuTNF. Romeo et al.(9) have reported previously that an antiviral state was induced in both FLC lines by IFN-γ, but only in FLC 745 by IFN-α/β. The present results suggest that the sensitivity to the synergistic cytotoxic effect of IFN and TNF in these cells is correlated with the ability to be induced into an antiviral state.

Journal Article
TL;DR: The results imply that CBA/N mice are not intrinsically resistant to FVA and that an as yet unknown type of immunological activity, evoked both by various immunizations and allogeneic transplantation, is required for Friend leukemogenesis in this immunodeficient inbred strain.
Abstract: CBA/N (xid-) mice failed to develop erythroleukemia when inoculated with an NB-tropic, anemia-causing Friend virus stock (FVA), while Fv-2ss mouse strains succumbed rapidly to the characteristic Friend disease, even after a virus dose 30-fold lower than that given to CBA/N mice. Immunization with bacterial antigens or with spleen cell allografts prior to FVA inoculation rendered CBA/N mice highly susceptible to FVA. Transplantation studies confirmed that non-immunized CBA/N mice were able to both support erythroleukemic cells and permit erythroleukemic transformation, thus arguing against host defense mechanisms as a cause of resistance. On the basis of early erythroid progenitor cell sensitivity to hydroxyurea in vivo, the CBA/N strain appeared to have the FVA sensitive genotype (Fv-2ss). These results imply that CBA/N mice are not intrinsically resistant to FVA and that an as yet unknown type of immunological activity, evoked both by various immunizations and allogeneic transplantation, is required for Friend leukemogenesis in this immunodeficient inbred strain. These findings further suggest that the erythroid target cells transformed by Friend viruses are influenced by immunological activity.

Journal ArticleDOI
TL;DR: In Friend leukemia virus-induced tumor cell lines derived from mice congenic with respect to the H-2 complex, most cell lines expressing theH-2k haplotype continuously produced infectious exogenous virus in culture, whereas most cell Lines expressing the H1b or H2d haplotype stopped producing virus during in vitro passage.
Abstract: In Friend leukemia virus-induced tumor cell lines derived from mice congenic with respect to the H-2 complex, most cell lines expressing the H-2k haplotype continuously produced infectious exogenous virus in culture, whereas most cell lines expressing the H-2b or H-2d haplotype stopped producing virus during in vitro passage. This apparent H-2-linked control of virus production did not appear to be the result of alteration of the provirus or resistance to superinfection. The implications of this finding with respect to virus-induced leukemogenesis are discussed. Images

Journal ArticleDOI
TL;DR: The incidence of leukemia was reduced in the males, but not in the females, while the latent period was prolonged in both sexes, indicating sex dependency is characteristic of the stress response.
Abstract: The effects of physical restraint on the development of Friend erythroleukemia in ddY mice were examined. Restraint was applied by immobilizing the mice in wire cages. In both sexes there was a reduction in the weight of the whole body, thymus and spleen, though the food intake was not reduced. The incidence of leukemia was reduced in the males, but not in the females, while the latent period was prolonged in both sexes. This sex dependency is characteristic of the stress response.

Journal Article
TL;DR: It is reported here that mice with FLV-dormant infections resist the accumulation of transplantedFLV-transformed erythroleukemia cells (FLC-745) and that FLC-745 cells persist in the spleen for a prolonged period and radiosensitivity of the protective immune response is confirmed.
Abstract: The immunobiology of Friend erythroleukemia virus (FLV) has been the focal point of much research into immunological control of leukemia. We have been studying a murine model in which a rapidly fatal FLV infection of DBA/2 mice is suppressed to a dormant state by treatment with statolon, a double stranded RNA extract of Mycoplasma stoloniferum . We report here that mice with FLV-dormant infections resist the accumulation of transplanted FLV-transformed erythroleukemia cells (FLC-745) and that FLC-745 cells persist in the spleen for a prolonged period. Winn assays revealed that the spleen of FLV-dormant mice contain radiosensitive T-lymphocytes with anti-FLC-745 cell activity. Whole body irradiation of FLV-dormant mice abrogated their resistance to transplanted FLC-745 cells and confirmed the radiosensitivity of the protective immune response.

Journal ArticleDOI
TL;DR: The mechanisms that presumably regulate the appearance of SIL resistance in Sendai infected FLC are discussed and the maintenance of the resistant phenotype of the clones requires the serial subcultivation of the cells in the presence of activated EGSV.