Prevention of spontaneous leukemia in AKR mice by type-specific immunosuppression of endogenous ecotropic virogenes.

Huebner, Robert J.; Gilden, Raymond V.; Toni, Robert; Hill, Richard W.; Trimmer, Roy W.; Fish, Donald C.; Sass, Bernard

doi:10.1073/pnas.73.12.4633

Cited by 45 publications

(12 citation statements)

References 14 publications

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“…Such serum would be expected to contain a complete range of antibodies directed against virion and virus-induced cell membrane antigens and, therefore, modulating and tumor-suppressive antibodies are more likely to be present than in a host immunized with single antigens. Prophylactic immunization of mice and passive transfer of antibodies against endogenous virus particles were reported to prevent spontaneous tumor emergence and endogenous virus expression (49,50). The role of humoral immunity in these tumor models still needs to be delineated; however, antibody may act to regulate virogene and oncogene expression at the cellular level by a mechanism similar to antigenic modulation.…”

Section: Discussionmentioning

confidence: 99%

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

Genovesi¹,

Marx²,

Wheelock³

1977

The Journal of Experimental Medicine

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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.

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Section: Discussionmentioning

confidence: 99%

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

Genovesi¹,

Marx²,

Wheelock³

1977

The Journal of Experimental Medicine

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“…We have used Friend virus (FV) (8), an immunosuppressive retroviral complex that induces erythroleukemia in adult immunocompetent mice (9)(10)(11)(12)(13). Previously, passive transfers of specific antisera have been demonstrated to disrupt or delay the early pathogenic and oncogenic processes induced by murine leukemia viruses including FV (14)(15)(16)(17). However, data from this lab demonstrated that spontaneous recovery from FV-induced disease in genetically resistant animals was dependent on cell-mediated responses (18) as well as humoral responses (9).…”

mentioning

confidence: 99%

Passive immunotherapy for retroviral disease: influence of major histocompatibility complex type and T-cell responsiveness.

Hasenkrug

Brooks²,

Chesebro³

1995

Proc. Natl. Acad. Sci. U.S.A.

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Administration of virus-specific antibodies is known to be an effective early treatment for some viral infections. Such immunotherapy probably acts by antibodymediated neutralization of viral infectivity and is often thought to function independently of T-cell-mediated immune responses. In the present experiments, we studied passive antibody therapy using Friend murine leukemia virus complex as a model for an immunosuppressive retroviral disease in adult mice. The results showed that antibody therapy could induce recovery from a well-established retroviral infection. However, the success of therapy was dependent on the presence of both CD4+ and CD8+ T lymphocytes. Thus, cellmediated responses were required for recovery from infection even in the presence of therapeutic levels of antibody. The major histocompatibility type of the mice was also an important factor determining the relative success of antibody therapy in this system, but it was less critical for low-dose than for high-dose infections. Our results imply that limited T-cell responsiveness as dictated by major histocompatibility genes and/or stage of disease may have contributed to previous immunotherapy failures in AIDS patients. Possible strategies to improve the efficacy of future therapies are discussed.

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“…These include inbred strains that spontaneously develop cancer (1)(2)(3)(4), rodents in which cancer is caused by intrauterine or postnatal exposure to chemical mutagens (5)(6)(7)(8)(9), and mice in which tumors are produced by viral or bacterial infection (10)(11)(12)(13). In addition, xenograft models that were generated by directly implanting cancer cell lines established from human tumors into mice have been widely used for drug discovery (14)(15)(16)(17).…”

Section: Preclinical Mouse Models Of Human Cancermentioning

confidence: 99%

Harnessing preclinical mouse models to inform human clinical cancer trials

Gutmann

Hunter-Schaedle

Shannon

2006

Journal of Clinical Investigation

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The urgent need for better cancer treatments has stimulated interest in employing small-animal models to evaluate potential drug therapies. Robust mouse models of many human cancers have been generated using sophisticated technologies for engineering germ-line mutations. As we enter into an age of targeted therapeutics, these strains provide novel platforms for validating new anticancer drugs, assessing therapeutic index, identifying surrogate markers of tumor progression, and defining epigenetic and environmental influences on tumorigenesis.The availability of strains of genetically engineered mice (GEM) that develop a spectrum of cancers similar to those found in humans offers an unprecedented opportunity to efficiently evaluate the efficacy and therapeutic index of novel anticancer therapies in preclinical models in advance of human trials. While straightforward in principle, executing preclinical studies in mice that allow for meaningful and immediate application to the treatment of human cancer is difficult. Moreover, the potential use of GEM cancer models to accelerate the process of bringing effective new treatments to patients is largely theoretical, as few examples exist in which mouse preclinical data has been successfully translated to clinical practice. The current development process for anticancer drugsTaking a drug from discovery to market is an arduous process that frequently takes longer than 15 years and costs more than $800 million. Most agents that are advanced into early-phase human clinical trials fail. Recent advances in the fields of cancer biology and high-throughput screening have identified numerous potential molecular targets for drug discovery; however, most of the proteins and pathways deregulated in cancer cells also have essential roles in normal cells. It is therefore difficult to predict when a drug will prove tumor-selective. Moreover, developing new therapies against specific molecular abnormalities in well-defined subsets of cancers can be prohibitively expensive. The use of GEM cancer models as an initial "filter" to identify tumors and molecular targets that, when inhibited, will selectively kill tumor cells is one potential strategy for streamlining the overall process of cancer drug development. Preclinical mouse models of human cancerNumerous small-animal models of human cancer have been generated. These include inbred strains that spontaneously develop cancer (1-4), rodents in which cancer is caused by intrauterine or postnatal exposure to chemical mutagens (5-9), and mice in which tumors are produced by viral or bacterial infection (10-13). In addition, xenograft models that were generated by directly implanting cancer cell lines established from human tumors into mice have been widely used for drug discovery (14-17). The major limitations of these explant models are the requirement for an immunocompromised host and the inability of these models to fully recapitulate the complex relationship between the tumor and its microenvironment (e.g., angiogenesis). Most importan...

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Prevention of spontaneous leukemia in AKR mice by type-specific immunosuppression of endogenous ecotropic virogenes.

Cited by 45 publications

References 14 publications

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

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

Passive immunotherapy for retroviral disease: influence of major histocompatibility complex type and T-cell responsiveness.

Harnessing preclinical mouse models to inform human clinical cancer trials

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