RESUMEN
Histiocytic sarcoma (HS) and histiocyte-associated lymphoma (HAL) of mice are difficult to distinguish histologically. Studies of multiple cases initially diagnosed as HS or HAL allowed us to define HS as round, fusiform, or mixed cell types that were F4/80+, Mac-2+, and PAX5-; that lacked markers for other sarcomas; and that had immune receptor genes in germline configuration. Two other subsets had clonal populations of lymphocytes. The first, HAL, featured malignant lymphocytes admixed with large populations of normal-appearing histiocytes. The second appeared to be composites of lymphoma and HS. Several cases suggestive of B myeloid-lineage plasticity were also observed.
Asunto(s)
Sarcoma Histiocítico/veterinaria , Linfoma/veterinaria , Ratones , Enfermedades de los Roedores/diagnóstico , Animales , Antígenos de Diferenciación/metabolismo , Biomarcadores de Tumor/metabolismo , Femenino , Galectina 3/metabolismo , Sarcoma Histiocítico/diagnóstico , Sarcoma Histiocítico/patología , Linfoma/diagnóstico , Linfoma/patología , Masculino , Muramidasa/metabolismo , Factor de Transcripción PAX5/metabolismo , Enfermedades de los Roedores/metabolismo , Enfermedades de los Roedores/patologíaRESUMEN
Over the period of a year, colitis was observed in 44 mice raised in a conventional nonspecific pathogen-free colony, 41 of these having concomitant retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS). The lesions varied from bacterial colonization to hyperplasia of colonic mucosa to severe, often fatal, ulceration. Citrobacter rodentium was isolated from the colon and/or liver of 2 mice with colitis. When C57BL/6 mice with or without MAIDS were given graded doses of the bacterium, only those with MAIDS developed colitis, and C rodentium was reisolated from their livers. Thus, mice with MAIDS can develop severe disease following opportunistic infection with an environmental contaminant of the colony that is nonpathogenic for normal adult mice.
Asunto(s)
Citrobacter rodentium/aislamiento & purificación , Colitis/veterinaria , Infecciones por Enterobacteriaceae/veterinaria , Síndrome de Inmunodeficiencia Adquirida del Murino/metabolismo , Animales , Colitis/microbiología , Colitis/virología , Infecciones por Enterobacteriaceae/microbiología , Infecciones por Enterobacteriaceae/virología , Histocitoquímica/veterinaria , Ratones , Ratones Endogámicos C57BL , Síndrome de Inmunodeficiencia Adquirida del Murino/virologíaRESUMEN
Hematopoietic neoplasms developing in AKXD recombinant inbred, NFS.V(+) and ICSBP knockout mice were assessed using morphologic, cytologic and molecular criteria that relate these disorders to human lymphoma and leukemia. Lymphoma types included precursor T-cell and B-cell lymphoblastic, small lymphocytic, splenic marginal zone, follicular, and diffuse large cell (DLCL). In addition to previously defined subtypes of DLCL composed of centroblasts or immunoblasts, two additional subtypes are defined here: lymphoblastic lymphoma like (LL) and lymphoma characterized by a histiocytic reaction (HS). DLCL(HS) were distinguished from true histiocytic lymphomas by the presence of clonal Ig gene rearrangements.
Asunto(s)
Linfoma no Hodgkin/patología , Animales , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T/genética , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma no Hodgkin/clasificación , Linfoma no Hodgkin/genética , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos DBA , Ratones Noqueados , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologíaRESUMEN
Studies of lymphoid neoplasms occurring in normal or genetically engineered mice have revealed parallels and differences to non-Hodgkin lymphomas (NHL) of humans. Some mouse lymphomas have strong histologic similarities to the human NHL subsets including precursor B- and T-cell lymphoblastic, small lymphocytic, splenic marginal zone, and diffuse large-cell B-cell lymphomas (DLCL); whether molecular parallels also exist is under study. Others mouse types such as sIg+ lymphoblastic B-cell lymphoma have no histologic equivalent in human NHL even though they share molecular deregulation of BCL6 with human DLCL. Finally, Burkitt lymphoma does not appear to occur naturally in mice, but it can be induced with appropriately engineered transgenes.
Asunto(s)
Linfoma no Hodgkin/clasificación , Linfoma no Hodgkin/patología , Animales , Linfoma de Burkitt/patología , Humanos , Cadenas Pesadas de Inmunoglobulina/metabolismo , Inmunofenotipificación , Cariotipificación , Linfoma de Células B/clasificación , Linfoma de Células B/patología , Linfoma de Células T/clasificación , Linfoma de Células T/patología , Ratones , Modelos Animales , Células Tumorales CultivadasRESUMEN
Splenic marginal zone B cells of humans and mice are anatomically positioned with specialized macrophages, dendritic and endothelial cells. Together, they function as the first line of defense against blood borne pathogens with a low triggering threshold for B cells providing a rapid proliferative and antibody response to infections. In humans, B cells with similar cytology and physical relations to follicles are found in lymph nodes and Peyer's patches. However, they also develop in mucosa-associated lymphoid tissue (MALT) and other sites, such as the thyroid and salivary gland, that normally lack organized lymphoid tissue. Chronic antigenic stimulation at these sites or in response to infection with Hepatitis C provides the milieu for mutations at FAS, API2/ML, TP53 and INK4a/p19ARF and the development of marginal zone lymphomas (MZL) in node, spleen and MALT. Only splenic MZL are seen in mice. A reduced threshold for triggering to proliferation may predispose the marginal zone B cell to neoplasia with mutations in genes regulating apoptosis playing a leading role.
Asunto(s)
Linfoma/patología , Bazo/citología , Animales , Apoptosis , Linfocitos B/citología , División Celular , Perros , Endotelio/citología , Humanos , Macrófagos/citología , RatonesAsunto(s)
Linfoma de Células B Grandes Difuso/patología , Animales , Animales Congénicos , Biomarcadores de Tumor/análisis , Cruzamientos Genéticos , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Reordenamiento Génico de Linfocito B , Humanos , Virus de la Leucemia Murina/patogenicidad , Linfoma de Células B Grandes Difuso/química , Linfoma de Células B Grandes Difuso/genética , Ratones , Ratones Endogámicos , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Especificidad de la Especie , Factores de Transcripción/genética , Translocación GenéticaRESUMEN
Spontaneous lymphomas occur at high frequency in NFS x V+ mice, strains congenic for ecotropic murine leukemia virus (MuLV) proviral genes and expressing virus at high titer. In the present study, a total of 703 NFS x V+ lymphomas were studied by histopathology, immunophenotypic analysis, immunoglobulin heavy chain or T cell receptor beta chain rearrangements, and somatic ecotropic MuLV integrations; 90% of the lymphomas tested were of B cell lineage. Low-grade tumors included small lymphocytic, follicular, and splenic marginal zone lymphomas, while high-grade tumors comprised diffuse large-cell (centroblastic and immunoblastic types), splenic marginal zone, and lymphoblastic lymphomas. Comparison of mice of similar genetic background except for presence (NFS x V+) or absence (NFS x V-) of functional ecotropic MuLV genomes showed that NFS x V-clonal lymphomas developed at about one-half the rate of those occurring in NFS x V+ mice, and most were low-grade B cell lymphomas with extended latent periods. In NFS x V+ mice, clonal outgrowth, defined by Ig gene rearrangements, was associated with acquisition of somatic ecotropic proviral integrations, suggesting that, although generation of B cell clones can be virus independent, ecotropic virus may act to increase the rate of generation of clones and speed their evolution to lymphoma. The mechanism remains undefined, because only rare rearrangements were detected in several cellular loci previously associated with MuLV insertional mutagenesis.
Asunto(s)
Virus de la Leucemia Murina/aislamiento & purificación , Linfoma de Células B/patología , Linfoma de Células B/virología , Animales , Southern Blotting , Reordenamiento Génico de la Cadena beta de los Receptores de Antígenos de los Linfocitos T , Genoma Viral , Cadenas Pesadas de Inmunoglobulina/genética , Inmunohistoquímica , Virus de la Leucemia Murina/genética , Linfoma de Células B/clasificación , Linfoma de Células B/genética , RatonesAsunto(s)
Linfoma de Células B/patología , Animales , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Expresión Génica , Humanos , Linfoma de Células B/genética , Ratones , Mutación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Factores de Transcripción/genéticaRESUMEN
Splenic marginal zone lymphomas (MZLs) have been found to occur at a high frequency in NFS.N mice congenic for high-expressing ecotropic murine leukemia virus (MuLV) genes from AKR and C58 mice. Based on morphological, immunological, and molecular studies of these mice, MZL is clearly recognizable as a distinct disease with a characteristic clinical behavior. MZL was staged according to the degree of accumulation and morphological change of cells within the splenic marginal zone, as follows: 1) a moderate increase in normal-looking MZ cells, judged to be prelymphomatous, and 2) MZL in three variants: i) distinct enlargement of MZ by normal-looking cells (MZL), ii) distinct enlargement of MZ by basophilic centroblast-like cells (MZL+), and iii) extensive splenic involvement by centroblast-like cells (MZL++). The rate of mitosis and apoptosis increases with lymphoma grade. In most cases, emergence of a dominant IgH clonal pattern in paired splenic biopsy and necropsy samples was correlated with progression. MZLs were transplantable and homed to the spleen. MZL may constitute a commonly occurring lymphoma type unrecognized, in part, because of the centroblastic morphology of high-grade MZL and possible overgrowth of lower-grade MZL by more aggressive follicular lymphomas.
Asunto(s)
Linfoma/patología , Neoplasias del Bazo/patología , Animales , Inmunofenotipificación , Linfoma/genética , Linfoma/inmunología , Ratones , Ratones Mutantes , Estadificación de Neoplasias , Bazo/patología , Neoplasias del Bazo/genética , Neoplasias del Bazo/inmunologíaRESUMEN
The G1 cyclin, cyclin D1, has been implicated in the development of human and mouse tumors. Here we describe immunohistochemical analyses of cyclin D1 for a large panel of mouse B cell tumors. In addition, we characterize cyclin D1 expression in a series of cultured cell lines that represent transformed B cells at different stages of development. Immunohistochemical analysis showed that for low-grade lymphomas, cyclin D1 was expressed by 83% of centroblastic centrocytic (CBCC) and 14% of small lymphocytic lymphomas (SLL). For high-grade tumors, 28% of B lymphoblastic and 23% of centroblastic tumors expressed cyclin D1, while all immunoblastic lymphomas were negative. Studies of RNA and protein prepared from cultured B lineage tumors showed that cyclin D1 was expressed by all pre-B and most B cell tumors but not by cell lines representative of late B cell differentiation or by plasma cells. Expression of cyclin D1 in the lymphomas was not associated with alterations in the genomic structure of the Fis-1 (Bcl-1) common proviral integration site or cyclin D1 itself or with cell growth activity as assessed by expression of proliferating cell nuclear antigen (PCNA).
Asunto(s)
Ciclina D1/genética , Linfoma de Células B/genética , Animales , Proteínas Portadoras/genética , Diferenciación Celular , ADN/análisis , Factor Proteico para Inverción de Estimulación , Expresión Génica , Genes myc/genética , Inmunohistoquímica , Factores de Integración del Huésped , Linfoma de Células B/química , Linfoma de Células B/patología , Linfoma de Células T/genética , Ratones , Hibridación de Ácido Nucleico , Antígeno Nuclear de Célula en Proliferación/biosíntesis , ARN Mensajero/análisis , Células Tumorales CultivadasRESUMEN
B cell malignancies arise with increased frequency in aging individuals and in patients with genetic or acquired immunodeficiency (e.g., AIDS) or autoimmune diseases. The mechanisms of lymphomagenesis in these individuals are poorly understood. In this report we investigated the possibility that mutations at the Fas (lpr) and Fasl (gld) loci, which prevent Fas-mediated apoptosis and cause an early onset benign lymphoid hyperplasia and autoimmunity, also predispose mice to malignant lymphomas later in life. Up to 6 mo of age, hyperplasia in lpr and gld mice results from the predominant accumulation of polyclonal T cell subsets and smaller numbers of polyclonal B cells and plasma cells. Here, we examined C3H-lpr, C3H-gld, and BALB-gld mice 6-15 mo of age for the emergence of clonal T and B cell populations and found that a significant proportion of aging mice exclusively developed B cell malignancies with many of the hallmarks of immunodeficiency-associated B lymphomas. By 1 yr of age, approximately 60% of BALB-gld and 30% of C3H-gld mice had monoclonal B cell populations that grew and metastasized in scid recipients but in most cases were rejected by immunocompetent mice. The tumors developed in a milieu greatly enriched for plasma cells, CD23- B cells and immunodeficient memory T cells and variably depleted of B220+ DN T cells. Growth factor-independent cell lines were established from five of the tumors. The majority of the tumors were CD23- and IgH isotype switched and a high proportion was CD5+ and dull Mac-1+. Considering their Ig secretion and morphology in vivo, most tumors were classified as malignant plasmacytoid lymphomas. The delayed development of the gld tumors indicated that genetic defects in addition to the Fas/Fasl mutations were necessary for malignant transformation. Interestingly, none of the tumors showed changes in the genomic organization of c-Myc but many had one or more somatically-acquired MuLV proviral integrations that were transmitted in scid passages and cell lines. Therefore, insertional mutagenesis may be a mechanism for transformation in gld B cells. Our panel of in vivo passaged and in vitro adapted gld lymphomas will be a valuable tool for the future identification of genetic abnormalities associated with B cell transformation in aging and autoimmune mice.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/inmunología , Glicoproteínas de Membrana/inmunología , Receptor fas/inmunología , Envejecimiento/inmunología , Animales , Subgrupos de Linfocitos B/citología , Proteína Ligando Fas , Virus de la Leucemia Murina/genética , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos MRL lpr , Ratones SCID , Fenotipo , Provirus/genética , Subgrupos de Linfocitos T/citología , Células Tumorales Cultivadas , Integración ViralRESUMEN
The results of this study demonstrate that murine cytomegalovirus (MCMV) induces polyclonal B cell activation in mice during the acute phase of primary infection. First flow cytometric analysis revealed that surface expression of CD45R, IgM, and IgK by splenocytes from MCMV-infected mice was significantly reduced with a concomitant increase in the frequency of surface IgG-expressing cells. Second, ELIspot assays demonstrated that the changes revealed by flow cytometry were paralleled by increases in the numbers of IgG-producing cells, especially those secreting IgG2a. Third, the IgG antibodies from MCMV-infected animals reacted against a variety of self and foreign antigens. MCMV-induced B cell activation was independent of CD4+ T-cell-mediated help and CD40, since activation was observed in two models of mice deficient for this T cell subset and in mice deficient for CD40. Reverse transcription-polymerase chain reaction analysis showed that mRNA transcripts for the cytokines IL-6, IL-10, and IFN-gamma were rapidly induced following infection with MCMV, but only IL-6 and IFN-gamma proteins were detectable by ELISA. In addition, the numbers of cells producing IL-6 and IFN-gamma were significantly increased in the spleen. The magnitude of the polyclonal B cell activation response was diminished by 50% in IL-6-deficient mice but not in mice lacking IFN-gamma. In the absence of IFN-gamma, surface expression and serum levels of IgG2a were reduced while IgG1 expression was increased.
Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/fisiología , Infecciones por Citomegalovirus/inmunología , Activación de Linfocitos , Muromegalovirus/inmunología , Células 3T3 , Animales , Especificidad de Anticuerpos , Antígenos CD40/genética , Citocinas/biosíntesis , Infecciones por Citomegalovirus/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígenos de Histocompatibilidad Clase II/fisiología , Inmunoglobulina G/análisis , Inmunoglobulina G/clasificación , Interferón gamma/deficiencia , Interferón gamma/fisiología , Interleucina-6/deficiencia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Ratones Desnudos , Especificidad de la Especie , Bazo/inmunología , Bazo/patologíaRESUMEN
BACKGROUND-MATERIALS: Mice with normal or impaired immune function were studied for responses to intranasal infection with MHV68, a gammaherpesvirus that acutely infects lung epithelial cells and establishes latency in B cells. Infection of normal mice induced a vigorous pulmonary inflammatory response composed of T, B, and NK cells and macrophages and stimulated activation and proliferation of T and B cells in spleen. METHODS-RESULTS-CONCLUSIONS: Resolution of the infection was associated with induction of MHV68-specific antibodies, but virus-specific cytotoxic T cells were not detected. Mice inoculated with retroviruses that induce severe immunodeficiency unexpectedly cleared MHV68 from lung in the same time-frame as controls and failed to develop latency as determined by infectious center tests of spleen cells. In contrast, control of MHV68 infection in spleen and/or lung was impaired in mice deficient in CD4+ or CD8+ T cells or both T cell subsets, B cells, IFN-gamma, or inducible nitric oxide synthase (iNOS). Infection was uniformly lethal in nude and iNOS-deficient mice and killed one-third of IFN-gamma-deficient mice. These results indicate that resistance to MHV68 is markedly influenced by expression of IFN-gamma from T cells leading to induction of iNOS and generation of nitric oxide.
Asunto(s)
Gammaherpesvirinae/inmunología , Infecciones por Herpesviridae/inmunología , Huésped Inmunocomprometido , Enfermedades Pulmonares/inmunología , Animales , Anticuerpos Antivirales/análisis , Linfocitos B/inmunología , Femenino , Infecciones por Herpesviridae/patología , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Enfermedades Pulmonares/patología , Activación de Linfocitos/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Mutantes , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/biosíntesis , Bazo/inmunología , Bazo/patología , Linfocitos T/inmunologíaRESUMEN
Recent analysis of over 500 lymphomas occurring in NFS.V mice, congenic for Akv-type ecotropic MuLV structural genes, has revealed that about 90% are of B cell lineage as determined by demonstration of clonal rearrangements of Ig heavy chain genes, phenotyping by immunocytochemistry or cytofluorometric analysis, and by site and morphology of tumor. At least 40% of the B cell lymphomas were found to have their origin in the splenic marginal zone, a site only once before described for mouse lymphomas. Clonal somatic integrations of ecotropic MuLV occurred in 85% of tumors.
Asunto(s)
Virus de la Leucemia Murina , Leucemia Experimental/virología , Linfoma/virología , Infecciones por Retroviridae/virología , Infecciones Tumorales por Virus/virología , Animales , Reordenamiento Génico , Cadenas Pesadas de Inmunoglobulina/genética , Inmunofenotipificación , Leucemia Experimental/fisiopatología , Linfoma/fisiopatología , Linfoma de Células B/inmunología , Linfoma de Células B/virología , Linfoma de Células T/virología , Ratones , Ratones Endogámicos , Infecciones por Retroviridae/fisiopatología , Infecciones Tumorales por Virus/fisiopatologíaRESUMEN
The mechanisms responsible for development of profound immunodeficiency and extensive lymphoproliferation that characterize infection of different species with retroviruses are only partially understood. In mice, it has been shown the activities of an unusual Gag protein are necessary and sufficient to induce these abnormalities in a syndrome designated mouse AIDS (MAIDS). Current studies suggest that complex, antigen-driven interactions between T cells and B cells result in polyclonal activation of both types of lymphocytes, aberrant cytokine production and late lymphomas.
Asunto(s)
Productos del Gen gag/inmunología , Virus de la Leucemia Murina/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/virología , Proteínas Virales/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Citocinas/deficiencia , Citocinas/genética , Virus Defectuosos/inmunología , Virus de la Leucemia Murina/metabolismo , Activación de Linfocitos , Ratones , Ratones Noqueados , Transcripción GenéticaRESUMEN
CD8+ T cells were previously shown to be important in preventing lymphoproliferation and immunodeficiency following infection of murine AIDS (MAIDS)-resistant mice with the LP-BM5 mixture of murine leukemia viruses. To further evaluate the mechanisms contributing to MAIDS resistance, we studied mice lacking CD8+ T cells or deficient in perforin due to knockout of the beta2-microglobulin (beta2M) or perforin gene, respectively. In contrast to wild-type, MAIDS-resistant controls, B10.A mice homozygous for the beta2M mutation and B10.D2 mice homozygous for the perforin mutation were diagnosed as having MAIDS by 5 to 8 weeks after infection by the criteria of lymphoproliferation, impaired proliferative responses to mitogens, and changes in cell populations as judged by histopathology and flow cytometry. Unexpectedly, there was no progression of lymphoproliferation through 24 weeks, even though immune functions were severely compromised. Expression of the defective virus responsible for MAIDS was enhanced in spleens of the knockouts in comparison with wild-type mice. These results demonstrate that perforin-dependent functions of CD8+ T cells contribute to MAIDS resistance but that other, non-CD8-dependent mechanisms are of equal or greater importance.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Virus de la Leucemia Murina/inmunología , Glicoproteínas de Membrana/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Microglobulina beta-2/inmunología , Animales , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Perforina , Proteínas Citotóxicas Formadoras de Poros , Microglobulina beta-2/genéticaRESUMEN
Immune activation in murine AIDS (MAIDS) has been suggested to involve a superantigen (SAG). The possibility that SAGs encoded by mammary tumor virus (MTV) might be the source of stimulation was studied by using Mtv mice. Mtv- mice developed typical MAIDS, excluding a requirement for Mtv-encoded SAGs in the pathogenesis of this disorder.
Asunto(s)
Antígenos Virales/inmunología , Virus de la Leucemia Murina/inmunología , Síndrome de Inmunodeficiencia Adquirida del Murino/inmunología , Superantígenos/inmunología , Animales , Línea Celular , Femenino , Masculino , Virus del Tumor Mamario del Ratón/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos CBARESUMEN
PURPOSE: This study investigates the feasibility of systemic gene delivery in a tumor-bearing host using a vaccinia virus-based in vivo gene delivery and expression system. METHODS: A recombinant vaccinia virus encoding human interleukin-1beta (hIL-1beta) was constructed with a strong synthetic vaccinia virus late promoter driving hIL-1beta gene expression. C57BL/6 mice bearing established subcutaneous pancreatic tumors were injected intravenously in a blinded, randomized fashion with different doses of either the recombinant vaccinia virus(vMJ601hIL-Ibeta), control vaccinia (wild-type or TK-deficient), or saline. Toxicity was assessed, serial tumor sizes were measured, and viral titers and the amount of hIL-1beta in tumor, liver, and spleen were determined. RESULTS: High viral titers (10(6) PFU/g) were detected in tumors for all three viruses on postinjection day 3, and tumor viral titers persisted at high levels until day 9. In contrast, viral titers were initially 104-fold lower in nontumor tissues and decreased to undetectable levels by day 9. vMJ60hIL-1beta was rapidly cleared from liver and spleen by day 3 (titer levels < 100 PFU/g), while tumor titer levels persisted at 8.5 x 10(6) PFU/g. hIL-1beta was measurable in three of three tumors from vMJ601hIL-1beta treated mice on postinjection day 3, one of three on day 6, and one of three on day 9; no hIL-1beta was detected in any other tumors or normal tissues. Wild-type vaccinia had no antitumor effects. Treatment with two different doses of vMJ601hIL-1beta resulted in a consistent and significant decrease in tumor size in repeatable experiments as compared to controls. Histologic analysis revealed tumor cell necrosis with a surrounding neutrophil infiltrate in the vMJ601hIL-1beta treated tumor. CONCLUSION: These data show that recombinant vaccinia virus encoding hIL-1beta given intravenously preferentially localizes and amplifies in tumor tissue, is rapidly cleared from liver and spleen, produces measurable hIL-1beta in tumor but not normal tissues, and inhibits growth of established solid tumors in mice. Recombinant vaccinia virus encoding therapeutic genes may be a practical, efficient vehicle for direct in vivo gene transfer and expression in the treatment of cancer.
Asunto(s)
Terapia Genética/métodos , Vectores Genéticos , Interleucina-1/genética , Neoplasias Experimentales/terapia , Neoplasias Pancreáticas/terapia , Virus Vaccinia , Animales , Expresión Génica , Humanos , Inmunohistoquímica , Interleucina-1/análisis , Hígado/virología , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/patología , Neoplasias Experimentales/virología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/virología , Proteínas Recombinantes , Bazo/virologíaRESUMEN
Murine acquired immunodeficiency syndrome (MAIDS), induce in mice by a defective murine retrovirus (BM5def), is characterized by development of severe immunodeficiency and polyclonal lymphoid proliferation which progress to yield oligoclonal populations of T and B cells. Oligoclonal populations transferred to SCID mice grew as clonal CD4+ T cell or B cell lineage transplants having one or more unique clonal integrations of BM5def. In some cases, spleens of single donor mice were shown to contain both B cell and T cell lineage clones that could be transferred individually after separation and were clonally unrelated. Successful transplants were obtained from oligoclonal populations as early as 63 days after infection. Mouse strains both sensitive or moderately resistant to MAIDS yielded clonal transplants.