Specific high-affinity binding of 125I-labeled mouse interferon to interfevon resistant embryonal carcinoma cells in vitro.
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Animals↗
Biomedical subjects
I Gresser
Publications and source records attributed to I Gresser.
Reversibility of the transformed and neoplastic phenotype. I. Progressive reversion of the phenotype of X-ray-transformed C3H/10T1/2 cells under prolonged treatment with interferon.
X-ray transformed mouse C3H/10T1/2 cells were cultivated and passaged in the continuous presence of partially purified mouse interferon. This prolonged interferon treatment resulted in a stepwise progressive reversion of the transformed phenotype to the non-transformed phenotype. Thus interferon-treated cells displayed an epithelioid morphology, grew to a lower cell density, and were no longer tumorigenic. Reversion to the non-transformed phenotype was, however, stable only as long as interferon was continuously present in the culture medium. When interferon was removed, the cells "back reverted" to the transformed phenotype. Our results suggest that interferon induced a reversion of the transformed phenotype in the entire cell population rather than a selection of an interferon resistant cell population. C-type viral particles and significant levels of reverse transcriptase were present in transformed cells, but neither present in the parental 10T1/2 cells nor in interferon-treated cells. When interferon was removed form the culture medium, viral particles and reverse transcriptase activity were again detected. It is possible, therefore, that interferon induces reversion through its antiviral activity, or that it induces reversion by its effects on cell function and structure, independently of any antiviral effect. Inhibition of cell multiplication per se does no appear to be sufficient to induce reversion, since cycloheximide inhibited cell multiplication; however, even after ten passages, it did not affect tumorigenicity. Our results suggest the possibility that interferon may act in vivo not only by inhibiting tumor cell multiplication but also by inducing a reversion. Patients with some tumors may therefore benefit from long-term interferon treatment.
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Virus-specific interferon action. Protection of newborn Mx carriers against lethal infection with influenza virus.
The efficacy of interferon in antiviral protection of newborn mice differing at the Mx locus was investigated. Adult mice bearing the allele Mx exhibit a high degree of specific resistance toward lethal challenge with influenza viruses. In contrast, newborn Mx carriers are virtually as susceptible to influenza viruses as newborn mice devoid of Mx. Resistance can be abrogated by treating adult animals with anti-interferon serum. Here, we provide direct evidence of a virus-specific effect of interferon in vivo: newborn mice carrying the resistance gene Mx could be protected against lethal influenza virus infection with doses of interferon that were not protective in the absence of Mx. The efficacy of interferon towards a picornavirus (encephalomyocarditis virus) and a rhabdovirus (vesicular stomatitis virus) was independent of Mx.
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Interferon enhances the amount of membrane-bound beta2-microglobulin and its release from human Burkitt cells.
Human leukocytes interferon (HuIFN-A) increased the amount of beta2-microglobulin on the surface of human Burkitt lymphoma cells (Ramos) and also increased the amount released into the culture medium. The effect was observed 1 h after addition of IFN. These results suggest that the increase in beta2-microglobulin on the cell surface of IFN-treated cells is not due to a decreased shedding of antigen from the cell surface, nor an "unmasking" of surface antigen, but rather to an increased synthesis of antigen.
Beta-Globulins↗
Variation of interferon induction at the bone marrow level. Studies on interferon induction in relation to natural cell-mediated cytotoxic mechanisms.
The effects of interferon inducers on different cytolytic mechanisms were studied in the high leukemia mouse strain AKR. A clear depression in baseline cytolytic potential and interferon-mediated stimulation of natural killer cell activities was demonstrated. This depression was most pronounced after 8 weeks of age. In contrast, antibody-dependent, cell-mediated cytotoxicity against IgG-coated chicken red blood cells was always normal. Bone marrow chimeras between CBA and AKR mice were produced to investigate the influence of bone marrow vs. host-mediated factors in these two strains with regard to interferon induction and cytolytic functions. Bone marrow genotype was found to be the dominating factor with regard to both parameters. Mice reconstituted with AKR bone marrow were deficient both in interferon production using tilorone and Newcastle disease virus as inducers, and at the level of natural killer cells responding to exogenously administered interferon. The possible relationship between these findings and the development of lymphomas in AKR mice is discussed.
Aging↗
Enhancement of Fc gamma receptor expression in interferon-treated mice.
Treatment of C3H mice with partially purified or highly purified virus-induced interferon resulted in a marked increase in the expression of Fcgamma receptors (Fcgamma R) on splenic lymphocytes, mesenteric lymph node cells and thymocytes from cortisone-treated mice. An increase on Fcgamma R on splenic lymphocytes was seen as early as 5 h and lasted at least 72 h after a single injection of interferon. We suggest that enhancement of Fcgamma R is one of the mechanisms by which interferon exerts some immunostimulating effects in vivo.
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Influence of anti-mouse interferon serum on the growth and metastasis of tumor cells persistently infected with virus and of human prostatic tumors in athymic nude mice.
Baby hamster kidney or HeLa cells form tumors in 100% of athymic nude mice. When such cells are persistently infected (PI) with RNA viruses, such as mumps or measles virus, the tumor cells either fail to grow or form circumscribed benign nodules. Neither the parental nor the virus PI tumor cells form invasive or metastatic lesions in nude mice. Previous studies have indicated a correlation between the susceptibility of virus-PI tumor cells in vitro and the cytolytic activity of natural killer (NK) cells and their failure to grow in vivo. Because interferon (IF) is the principal regulatory molecule governing the differentiation of NK cells, it was possible to test the relevance of the IF-NK cell system in vivo to restriction of tumor growth by treatment of nude mice with anti-IF globulin. This treatment was shown to reduce both IF production and NK activity in spleen cells. Both parental and virus-PI tumor cells grew and formed larger tumors in nude mice treated with anti-IF globulin than in control nude mice. The viral-PI tumor cells and the uninfected parental cells formed tumors in treated mice that were highly invasive and often metastatic. Some human tumor types have been notoriously difficult to establish as tumor lines in nude mice (e.g., primary human prostatic carcinomas). When transplanted into nude mice treated either with anti-IF globulin or anti-lymphocyte serum, two prostatic carcinomas grew and produced neoplasms with local invasiveness and some metastases. The results are consistent with the view that interferon may be important in restricting the growth, invasiveness, and metastases of tumor cells by acting indirectly through components of the immune system, such as NK cells.
Animals↗
Hypoglycemia in mice injected with interferon inducers is not mediated by interferon.
Injection of mice with several viral and nonviral inducers of interferon resulted in a marked hypoglycemia. Interferon is not responsible for this effect since inoculation of a potent antiserum to interferon (which neutralized the endogenous interferon) did not prevent hypoglycemia and administration of potent interferon preparations did not lower blood sugar. Hypoglycemia induced by Newcastle disease virus and polyriboinosinic-polyribocytidylic acid was further exacerbated by injection of insulin.
Animals↗
Electrophoretically pure mouse interferon inhibits growth, induces liver and kidney lesions, and kills suckling mice.
Suckling Swiss mice were injected daily for 8 days with either electrophoretically pure (EP) mouse interferon (s.a. 4.7 x 10(8) units/mg protein), major impurities obtained in the course of purification, or partially purified mouse interferon (s.a. 1.3 x 10(7) units/mg protein). Only EP or partially purified interferon inhibited growth, induced liver and kidney lesions, and killed mice. The authors conclude that interferon itself is responsible for these effects.
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Interferon induces peripheral lymphadenopathy in mice.
Inoculation (i.p. or i.v.) of partially purified or highly purified (H.P.) mouse interferon (electrophoretically pure in SDS-PAGE gels) into different strains of mice (C3H, BALB/c, Swiss, heterozygote and athymic nu/nu C57BL/6) results in a marked increase in the weight and in the total number of cells in axillary and inguinal lymph nodes. Interferon injected into the hind footpad induced an increase in the weight of the ipsilateral popliteal lymph node compared with the contralateral lymph node. Inoculation of noninterferon proteins (impurities) obtained in the course of purification of this H.P. interferon, mock interferon, or human leukocyte interferon were without effect. Experiments were undertaken to elucidate the mechanism by which interferon induced an increase in the weight (number of cells) of peripheral lymph nodes. There was no evidence that the afflux of transferred chromium-labeled lymphoid cells to lymphoid tissue was increased in interferon-treated recipient mice. There was no evidence that interferon treatment resulted in a stimulation of the multiplication of cells within the peripheral lymph nodes. Since we observed a decrease in the number of lymphocytes in the thoracic duct lymph and in the peripheal blood of interferon-treated mice, we suggest that interferon treatment resulted in an inhibition of egress of lymphocytes from lymphoid tissue. The finding that interferon treatment of mice alters patterns of lymphocyte circulation may be relevant to some of the effects of interferon on the immune system and may explain in part the lymphadenopathy observed in the course of some viral infections.
Animals↗
Severity of lymphocytic choriomeningitis virus disease in different strains of suckling mice correlates with increasing amounts of endogenous interferon.
A marked difference was observed in the severity of disease in lymphocytic choriomeningitis (LCM) virus-infected suckling BALB/c, Swiss, and C3H mice. BALB/c mice had minimal liver lesions and none died, whereas C3H mice had extensive liver lesions and all mice died. An intermediate pattern was oberved for Swiss mice (36% mortality). Although there was no difference in the titers of LCM virus in the plasma or liver between these three strains of mice, there was a marked difference in the amount of interferon produced and the duration of interferonemia. C3H mice produced more interferon than Swiss mice which produced more interferon than BALB/c mice, indicating a direct correlation between the amount of interferon induced by LCM virus and the extent of disease. Inoculation of a potent anti-mouse interferon globulin markedly reduced the incidence of mortality in virus-infected C3H mice. BALB/c mice were as sensitive to the effects of interferon as C3H mice because daily administration of potent interferon preparations did induce disease in this strain. This ensemble of results supports our contention that endogenous interferon is in large part responsible for the manifestaions of acute LCM virus disease in suckling mice.
Animal Population Groups↗
Host gene influences sensitivity to interferon action selectively for influenza virus.
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Animals↗
Effect of virus-induced interferon on the antibody response of suckling and adult mice.
Continued administration of potent virally induced mouse interferon (IFN type I) preparations to suckling mice resulted in an inhibition of the primary antibody response to sheep erythrocytes (14-day-old mice). When slightly older suckling mice were immunized (17 days old), a delay (about 2 days) in the kinetics of the response was observed, but the amplitude of the response was similar in both control and IFN-treated animals. In adult mice, potent IFN preparations did not inhibit the antibody response under a variety of experimental conditions (different doses of IFN, schedules of treatment, routes of injection, times of assay). Although IFN does inhibit the in vitro antibody response, we conclude that under most experimental conditions, injection of IFN type I is not immunosuppressive in adult mice. When administered after immunization, IFN clearly enhanced the primary antibody response. It is of interest that IFN, a product of viral infection, enhances in vivo those components of the immune system that have been implicated in the host response to viral infections (i.e. delayed-type hypersensitivity, natural killer cell and macrophage activity, expression of lymphocyte membrane molecules), and, as is shown here, the primary antibody response.
Aging↗
Usefulness of the results of studies on the antitumor effects of interferon in animals to interferontherapy of patients.
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Animals↗
Interferon-induced disease in mice and rats.
Treatment of newborn mice with potent mouse interferon preparations resulted in an acute "early" syndrome characterized by inhibition of growth, delay in maturation of several organs, diffuse liver cell necrosis and death. When interferon treatment was discontinued at 1 week of life, mice appeared to recover, but subsequently developed a progressive glomerulonephritis ("late syndrome"). Treatment of newborn rats with potent rat interferon preparations also resulted in inhibition of growth, delay in maturation, and the subsequent development of glomerulonephritis. After infection at birth with lymphocyte choriomeningitis (LCM) virus, most strains of mice developed a similar acute early syndrome and surviving mice subsequently developed glomerulonephritis. We postulated that the endogenous interferon induced by LCM virus early in life was partially responsible for these syndromes. Administration of a potent anti-mouse interferon serum to LCM virus-infected mice neutralized the circulating endogenous interferon and inhibited the development of both the early and late syndromes. Our results suggest that large amounts of exogenous or endogenous interferon at a crucial stage of rapid growth or development of mice and rats can induce lesions in several different organs. Some lesions (i.e. the kidney) only become apparent weeks or even months after exposure to interferon.
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Electrophoretically pure mouse interferon exerts multiple biological effects.
Electrophoretically pure (EP) mouse interferon (IF), was examined for a number of biological effects of previously ascribed to crude or partially purified interferon preparations. The following effects were observed: inhibition of antibody formation in vitro; inhibition or enhancement of sensitization to sheep erythrocytes in the mouse, depending on time of administration of IF, and dosage of antigen; inhibition of the expression of delayed type hypersensitivity in vivo; enhancement of natural killer cell activity in vitro and in vivo; inhibition of mouse tumor cells multiplication in vitro; inhibition of the growth of a transplantable tumor in mice. EP mouse IF had a very pronounced priming effect but had no blocking activity.
Animals↗
Interaction between interferon and host genes in antiviral defense.
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Animals↗
Interferon enhances the expression of Fc gamma receptors.
Murine T2D4 cells derived from a T cell hybrid line were incubated with partially purified or electrophoretically pure mouse interferon and tested for the expression of Fc gamma R as assessed by a) counting the number of cells forming rosettes with IgG-sensitized sheep erythrocytes, and b) incubating the cells with heat-aggregated rabbit IgG and then determining either the number of cells stained with fluorescein conjugated goat anti-rabbit IgG or the extent of labeling by using radioactive iodinated staphylococcus protein A. Although interferon induced a rapid increase in Fc gamma R expression on the Fc gamma R-positive T2D4 cells, it did not induce either Fc gamma R on the Fc gamma R negative BW5147 cells or Fc gamma R on either cell line. Human leukocyte interferon enhanced the expression of Fc gamma R on human Burkitt cells (Daudi) but did not affect the expression of Fc gamma R on mouse cells. We suggest that interferon may influence several effector functions of the immune system by modulating Fc receptor expression.
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