RESUMEN
Interleukin (IL)-4, a crucial modulator of the immune system and an active antitumor agent, is also a potent inhibitor of angiogenesis. When incorporated at concentrations of 10 ng/ml or more into pellets implanted into the rat cornea or when delivered systemically to the mouse by intraperitoneal injection, IL-4 blocked the induction of corneal neovascularization by basic fibroblast growth factor. IL-4 as well as IL-13 inhibited the migration of cultured bovine or human microvascular cells, showing unusual dose-response curves that were sharply stimulatory at a concentration of 0.01 ng/ml but inhibitory over a wide range of higher concentrations. Recombinant cytokine from mouse and from human worked equally well in vitro on bovine and human endothelial cells and in vivo in the rat, showing no species specificity. IL-4 was secreted at inhibitory levels by activated murine T helper (TH0) cells and by a line of carcinoma cells whose tumorigenicity is known to be inhibited by IL-4. Its ability to cause media conditioned by these cells to be antiangiogenic suggested that the antiangiogenic activity of IL-4 may play a role in normal physiology and contribute significantly to its demonstrated antitumor activity.
Asunto(s)
Inmunosupresores/farmacología , Interleucina-4/fisiología , Neovascularización Fisiológica/inmunología , Adenocarcinoma , Animales , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Células Cultivadas , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Córnea/inmunología , Medios de Cultivo Condicionados/química , Medio de Cultivo Libre de Suero/química , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Humanos , Inyecciones Intraperitoneales , Interleucina-4/administración & dosificación , Neoplasias Mamarias Experimentales , Ratones , Ratones Endogámicos BALB C , Neovascularización Fisiológica/efectos de los fármacos , Ratas , Células Tumorales CultivadasRESUMEN
We have used differential cDNA display to search for genes whose expression correlates with an aggressive phenotype in variants of the B16 murine melanoma line, B16-F1 and B16-F10. This analysis identified a novel gene, termed melastatin, that is expressed at high levels in poorly metastatic variants of B16 melanoma and at much reduced levels in highly metastatic B16 variants. Melastatin was also found to be differentially expressed in tissue sections of human melanocytic neoplasms. Benign nevi express high levels of melastatin, whereas primary melanomas showed variable melastatin expression. Melastatin transcripts were not detected in melanoma metastases. Within the set of human primary cutaneous melanomas examined, melastatin expression appeared to correlate inversely with tumor thickness. The expression pattern observed suggests that loss of melastatin expression is an indicator of melanoma aggressiveness.
Asunto(s)
ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Melanoma/genética , Melanoma/secundario , Oncogenes , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN de Neoplasias/metabolismo , Regulación hacia Abajo , Humanos , Melanoma/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/metabolismo , Melanoma Experimental/secundario , Ratones , Datos de Secuencia Molecular , Pronóstico , Células Tumorales CultivadasRESUMEN
Ligation of the cell surface receptor Fas/APO-1 (CD95) by its specific ligand or by anti-Fas antibodies rapidly induces apoptosis in susceptible cells. To characterize the molecular events involved in Fas-induced apoptosis, we examined the contribution of two subgroups of the mitogen-activated protein (MAP) kinase family, the Jun kinases or stress-activated protein kinases (JNKs/SAPKs) and the extracellular signal-regulated kinases (ERKs), in a Fas-sensitive neuroblastoma cell line. Here we show that both JNK and ERK protein kinases were activated upon Fas crosslinking through a Ras-dependent mechanism. Interference with either the JNK or ERK pathway by ectopic expression of dominant-interfering mutant proteins blocked Fas-mediated apoptosis. ERK activation was transient and associated with induced expression of the Fas receptor. In contrast, JNK activation was sustained and correlated with the onset of apoptosis. These data indicate that the ERK and the JNK groups of MAP kinases cooperate in the induction of cell death by Fas. Inhibition of Fas killing by an interleukin 1beta-converting enzyme (ICE)-like protease inhibitor peptide did not modify Fas-induced JNK activation upon Fas ligation. In contrast, changes in Bcl-2 level due to expression of sense and antisense vectors influenced the sensitivity to Fas killing and Fas-induced JNK activation.
Asunto(s)
Apoptosis , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Transducción de Señal , Receptor fas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Activación Enzimática , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Células Tumorales CultivadasRESUMEN
Pathogenic mycobacteria survive within macrophages despite T cell responses that activate host defenses against most pathogens. Among cytokines produced by T cells, IL-10 is known to negatively regulate Th1 cells as well as macrophages. IL-10 has been shown to inhibit the anti-mycobacterial activity of macrophages in vitro and could account for the ability of mycobacteria to survive intracellularly. To test the inhibitory functions of IL-10 in vivo, transgenic mice that secrete IL-10 from the T cell compartment were constructed and infected with Calmette-Guérin bacillus (Mycobacterium bovis). These mice were unable to clear the infection and developed large bacterial burdens. Nonetheless, their T cells produced abundant amounts of IFN-gamma and IL-2 in response to Ag challenge. These results indicate that the presence of excess IL-10 had little, if any, effect on T cell function or development during the immune response to Calmette-Guérin bacillus. Rather, the data suggest that IL-10 helps maintain mycobacterial infections by acting primarily at the level of the macrophage, overriding anti-mycobacterial signals delivered by IFN-gamma.
Asunto(s)
Regulación hacia Abajo/efectos de los fármacos , Interleucina-10/biosíntesis , Interleucina-10/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Mycobacterium bovis/efectos de los fármacos , Mycobacterium bovis/inmunología , Linfocitos T/metabolismo , Transgenes/genética , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Interferón gamma/biosíntesis , Interleucina-10/genética , Interleucina-2/biosíntesis , Ratones , Ratones Transgénicos , Mycobacterium bovis/patogenicidad , Tuberculosis/tratamiento farmacológico , Tuberculosis/inmunologíaRESUMEN
OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.
Asunto(s)
Proteínas Portadoras/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Mutación Puntual , Proteínas/metabolismo , Receptores de Superficie Celular , Receptores de Citocinas/genética , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Cartilla de ADN/genética , ADN Complementario/genética , Humanos , Leptina , Ratones , Ratones Endogámicos , Ratones Obesos , Datos de Secuencia Molecular , Obesidad/genética , Obesidad/metabolismo , Fenotipo , Reacción en Cadena de la Polimerasa , Receptores de Leptina , Homología de Secuencia de Aminoácido , Transducción de SeñalRESUMEN
The ob gene product, leptin, is an important circulating signal for the regulation of body weight. To identify high affinity leptin-binding sites, we generated a series of leptin-alkaline phosphatase (AP) fusion proteins as well as [125I]leptin. After a binding survey of cell lines and tissues, we identified leptin-binding sites in the mouse choroid plexus. A cDNA expression library was prepared from mouse choroid plexus and screened with a leptin-AP fusion protein to identify a leptin receptor (OB-R). OB-R is a single membrane-spanning receptor most related to the gp130 signal-transducing component of the IL-6 receptor, the G-CSF receptor, and the LIF receptor. OB-R mRNA is expressed not only in choroid plexus, but also in several other tissues, including hypothalamus. Genetic mapping of the gene encoding OB-R shows that it is within the 5.1 cM interval of mouse chromosome 4 that contains the db locus.
Asunto(s)
Obesidad/genética , Proteínas/genética , Secuencia de Aminoácidos , Animales , Sitios de Unión/fisiología , Plexo Coroideo/fisiología , Plexo Coroideo/ultraestructura , Mapeo Cromosómico , Clonación Molecular , Expresión Génica/fisiología , Humanos , Leptina , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Datos de Secuencia Molecular , Obesidad/metabolismo , Proteínas/aislamiento & purificación , Proteínas/metabolismo , ARN Mensajero/análisis , Receptores de Superficie Celular/aislamiento & purificación , Receptores de LeptinaRESUMEN
We have achieved efficient transduction of tumour metastases in vivo by the vascular delivery of retroviral producer cells. Experimental liver metastases in mice were created by intrasplenic injection of tumour cells into the portal venous circulation. Following the establishment of micrometastases, delivery of retroviral producer cells by the same route with a vector containing the Escherichia coli beta-galactosidase (lacZ) gene demonstrated selective in vivo gene transfer to tumour deposits. By this approach, two retroviral producer cell lines encoding cytokines (IL-4 and IL-2) directed tumoricidal inflammatory responses to established metastases. Cytokine gene targeting inhibited metastasis formation and caused significant overall reduction in tumour burden. These results suggest a novel therapeutic approach for the treatment of disseminated cancer.
Asunto(s)
Marcación de Gen , Terapia Genética , Interleucina-2/genética , Interleucina-4/genética , Neoplasias Hepáticas/secundario , Retroviridae/genética , Células 3T3 , Animales , Femenino , Técnicas de Transferencia de Gen , Interleucina-2/uso terapéutico , Interleucina-4/uso terapéutico , Operón Lac , Neoplasias Hepáticas/terapia , Masculino , Ratones , Células Tumorales CultivadasRESUMEN
We review a new technique--diamine oxidase (DAO)-gold ultrastructural enzyme-affinity labeling--which we developed to localize histamine in subcellular sites of mast cells. The DAO-gold method showed that isolated human lung mast cells contained abundant histamine in their cytoplasmic granules, a conclusion which was verified by a large number of specificity controls. We also studied mast-cell-rich eyelid lesions which developed in interleukin-4 transgenic mice. The DAO-gold method demonstrated histamine in the electron-dense granules of mast cells in these lesions, but little or no histamine was detected in the swollen, empty granules of mast cells undergoing piecemeal degranulation. This new enzyme-affinity-gold method has permitted the first ultrastructural localization of histamine in subcellular sites of routinely prepared electron microscopy samples. The method has also permitted the first morphological studies of histamine secretion in vivo and has demonstrated that such secretion can be associated with the ultrastructural changes of piecemeal degranulation.
Asunto(s)
Marcadores de Afinidad , Amina Oxidasa (conteniendo Cobre) , Exocitosis/fisiología , Oro , Liberación de Histamina/fisiología , Histamina/análisis , Mastocitos/fisiología , Animales , Blefaritis/patología , Gránulos Citoplasmáticos/química , Gránulos Citoplasmáticos/ultraestructura , Humanos , Interleucina-4/genética , Interleucina-4/fisiología , Pulmón/citología , Mastocitos/química , Mastocitos/ultraestructura , Ratones , Ratones Transgénicos , Microscopía Electrónica , Fijación del TejidoRESUMEN
Intratumoral grafting of genetically engineered cells that produce interleukin-4 (IL-4) has been shown to produce tumor regression as well as prolong survival of mice harboring intracerebral gliomas. We sought to determine whether retroviral-mediated gene delivery into tumor cells in situ resulted in enhanced tumor regression by IL-4. Two mouse fibroblast lines were obtained: they both secreted similar levels of IL-4 but one produced a retrovirus vector bearing the IL-4 gene (CRE-MFG-IL-4 cells), whereas the other did not (NIH3T3-IL-4 cells). In mixed transplantation assays in the subcutaneous flanks of athymic mice, CRE-MFG, IL-4 cells were more effective than NIH3T3-IL-4 cells in inhibiting the growth of rat C6 glioma cells (p < 0.005, ANOVA). Subcutaneous tumors injected with fibroblasts that produced a control retrovirus vector without producing IL-4 (CRE-MFG-LacZ cells) did not inhibit subcutaneous tumor growth. An intracranial assay was used to evaluate survival of athymic mice harboring intracranial gliomas. Three days after implanting rat C6 glioma cells into the right frontal lobes of athymic mice, NIH3T3-IL-4 cells (n = 10) or CRE-MFG-IL-4 cells (n = 10) were stereotactically inoculated into the tumor bed. The average survival of mice treated with CRE-MFG-IL-4 cells was 38 days (+/- 2.4, SE), whereas that of mice treated with NIH3T3-IL-4 cells was 31 days (+/- 0.8, SE) (p < 0.005, ANOVA; p < 0.001, log-rank analysis).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Células 3T3/trasplante , Neoplasias Encefálicas/terapia , Terapia Genética , Glioma/terapia , Factores Inmunológicos/uso terapéutico , Interleucina-4/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Células 3T3/metabolismo , Células 3T3/virología , Animales , Neoplasias Encefálicas/patología , Eosinofilia/etiología , Lóbulo Frontal , Vectores Genéticos/genética , Vectores Genéticos/fisiología , Glioma/patología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/genética , Factores Inmunológicos/metabolismo , Inyecciones Intralesiones , Interleucina-4/administración & dosificación , Interleucina-4/genética , Interleucina-4/metabolismo , Ratones , Ratones Desnudos , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Técnicas Estereotáxicas , Replicación ViralRESUMEN
In this report, we present evidence that the CTL response directed against MHC Class I allo-determinants can be inhibited as a result of IL-10 expression in vivo. The presence of localized IL-10 secretion at the site of allogeneic tumor cell challenge resulted in marked inhibition of the CTL response and allowed growth of the tumor in the allogeneic host. Using purified CD4+ T cells from mice immunized in the presence or absence of IL-10, we have shown that the loss of alloreactivity as a consequence of IL-10 expression results from the inhibition of CD4+ T cell function. The expression of either IL-2 or IFN-gamma with IL-10 locally at the time of allogeneic cell challenge completely restored CTL alloreactivity, suggesting that the action of IL-10 could be bypassed by providing helper T lymphocyte-derived cytokines of the Th1 type at the site of immunization. Inhibition of alloreactivity by IL-10 was observed using either purified macrophages or dendritic cells as APC in an in vitro assay. Thus, the expression of IL-10 following antigenic challenge (such as that observed in Th2-like immune responses) may profoundly limit the ability for generating functional CTL in vivo.
Asunto(s)
Interleucina-10/inmunología , Isoantígenos/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Anticuerpos Monoclonales , Linfocitos T CD4-Positivos/inmunología , Clonación Molecular , Pruebas Inmunológicas de Citotoxicidad , Células Dendríticas/inmunología , Técnica del Anticuerpo Fluorescente , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-10/biosíntesis , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Macrófagos Peritoneales/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Ratones , Ratones Endogámicos BALB C , Transfección/inmunología , Células Tumorales Cultivadas/inmunologíaRESUMEN
We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo.
Asunto(s)
Blefaritis/patología , Degranulación de la Célula , Párpados/ultraestructura , Liberación de Histamina , Interleucina-4/fisiología , Mastocitos/metabolismo , Amina Oxidasa (conteniendo Cobre) , Animales , Blefaritis/metabolismo , Párpados/metabolismo , Interleucina-4/genética , Mastocitos/ultraestructura , Ratones , Ratones Transgénicos , Microscopía Electrónica , Serotonina/metabolismoRESUMEN
Cytokines are key modulators of host immune and inflammatory responses. The expression of cytokine genes by tumor cells as a result of gene transfer has emerged as a novel strategy to augment in vivo host reactivity to various cancers. This review summarizes the knowledge obtained from experimental systems using this strategy and provides information on the current clinical trials employing this approach. In murine model systems, immunization with tumors expressing certain cytokines [e.g., tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-7 (IL-7), and granulocyte-macrophage colony stimulating (GM-CSF)] has demonstrated their ability to promote the generation of tumor-specific cytotoxic T lymphocytes by various mechanisms; in some cases, significant regressions of established microscopic tumor deposits result. Non T cell mechanisms of tumor killing, such as granulocytic inflammatory responses, may also be elicited by the localized elaboration of certain cytokines [e.g., IL-4, granulocyte colony-stimulating factor (G-CSF)]. The potency of antitumor immune potentiation by cytokines, however, remains to be established by further animal studies and emerging clinical trials. The genetic modification of tumors for the expression of immunostimulatory gene products holds promise as a new approach for active immunotherapy of cancer and for the isolation of effector cell populations for use in adoptive immunotherapy protocols.
Asunto(s)
Citocinas/genética , Inmunoterapia Adoptiva , Neoplasias/terapia , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Citocinas/fisiología , Citotoxicidad Inmunológica , Humanos , Neoplasias Experimentales/terapia , Fenotipo , Proteínas Recombinantes de Fusión , Inducción de Remisión , Proyectos de Investigación , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Three vectors derived from retrovirus, herpes simplex virus type 1 (HSV), and adenovirus were compared in cultured rat 9L gliosarcoma cells for gene transfer efficiency and in a 9L rat brain tumor model for histologic pattern and distribution of foreign gene delivery, as well as for associated tumor necrosis and inflammation. At a multiplicity of infection of 1, in vitro transfer of a foreign gene (lacZ from Escherichia coli) into cells was more efficient with either the replication-defective retrovirus vector or the replication-conditional thymidine kinase (TK)-deficient HSV vector than with the replication-defective adenovirus vector. In vivo, stereotactic injections of each vector into rat brain tumors revealed three main histopathologic findings: (i) retrovirus and HSV vector-mediated gene transfer was relatively selective for cells within the tumor, whereas adenovirus vector-mediated gene transfer occurred into several types of endogenous neural cells, as well as into cells within the tumor; (ii) gene transfer to multiple infiltrating tumor deposits without apparent gene transfer to intervening normal brain tissue occurred uniquely in one animal inoculated with the HSV vector, and (iii) extensive necrosis and selective inflammation in the tumor were evident with the HSV vector, whereas there was minimal evidence of tumor necrosis and inflammation with either the retrovirus or adenovirus vectors.
Asunto(s)
Adenovirus Humanos/genética , Neoplasias Encefálicas/terapia , Vectores Genéticos , Gliosarcoma/terapia , Proteínas Recombinantes de Fusión/biosíntesis , Retroviridae/genética , Simplexvirus/genética , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Gliosarcoma/genética , Gliosarcoma/patología , Inflamación , Masculino , Necrosis , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/microbiología , Neuroglía/metabolismo , Neuroglía/microbiología , Neuronas/metabolismo , Neuronas/microbiología , Ratas , Ratas Endogámicas F344 , Proteínas Recombinantes de Fusión/genética , Células Tumorales CultivadasRESUMEN
The ability of interleukin-4 (IL-4) to mediate an antitumor response to human gliomas was studied in vivo in nude mice. To allow the effect of IL-4 to be exerted over a relatively short distance and at an optimal concentration, a transfected tumor cell line expressing a high level of IL-4 was used in mixed tumor transplantation assays. There was a significant inhibition of growth of the U87 human glioma line when the IL-4-secreting cell line, LT-1, was implanted s.c. with the glioma in 5 nude mice when compared to contralateral control tumors consisting of the U87 glioma and IL-4-negative control cells. In addition, there was a prolongation of survival when U87 along with IL-4-secreting cells were implanted intracerebrally in 12 nude mice compared to 12 control nude mice implanted with U87 and IL-4-negative control cells and 11 control animals receiving U87 alone. Histological analysis 4 days after i.c. inoculation revealed the presence of a dramatic eosinophil infiltrate and tumor necrosis. The absence of viable glioma cells as well as resolution of inflammation 19 days after treatment suggests the potential for complete tumor regression without ongoing inflammatory sequelae resulting from cytokine treatment.
Asunto(s)
Neoplasias Encefálicas/terapia , Glioma/terapia , Inmunoterapia , Interleucina-4/metabolismo , Plasmacitoma/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Femenino , Humanos , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Interleucina-4/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Trasplante de Neoplasias , Plasmacitoma/patología , Ratas , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologíaRESUMEN
To investigate the role of interleukin 7 (IL-7) in the development of the lymphoid system, we have generated two lines of transgenic mice carrying an IL-7 cDNA fused to an immunoglobulin heavy chain promoter and enhancer. This transgene is expressed in the bone marrow, lymph nodes, spleen, thymus, and skin provoking a perturbation of T cell development characterized by a marked reduction of CD4+ CD8+ (double-positive) thymocytes. Quite unexpectedly, however, both lines also develop a progressive cutaneous disorder involving a dermal lymphoid infiltrate that results in progressive alopecia, hyperkeratosis, and exfoliation. Although the infiltrate is primarily composed of T lineage cells, its development is not impeded in the athymic nu/nu background. Furthermore, the phenotype can be transmitted horizontally by transplanting lymphoid tissues or skin to syngeneic wild-type mice. Thus, the phenotype is conveyed by skin-homing, mobile cells (presumably the infiltrating lymphocytes) in a cell-autonomous fashion. In addition to the skin phenotype, this transgene also provokes the development of a lymphoproliferative disorder that induces B and T cell lymphomas within the first 4 mo of life. These findings suggest potential physiologic actions of IL-7 in T cell development and in cutaneous immunity. They also demonstrate that IL-7 can act as an oncogene in the living organism.
Asunto(s)
Interleucina-7/fisiología , Linfoma/etiología , Enfermedades de la Piel/etiología , Neoplasias Cutáneas/etiología , Alopecia/etiología , Animales , Antígenos CD/análisis , Antígenos de Superficie/análisis , Complejo CD3/análisis , Antígenos CD5 , División Celular , Expresión Génica , Reordenamiento Génico de Linfocito B , Reordenamiento Génico de Linfocito T , Genes de Inmunoglobulinas , Activación de Linfocitos , Subgrupos Linfocitarios/citología , Linfoma/patología , Glicoproteínas de Membrana/análisis , Ratones , Ratones Transgénicos , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Enfermedades de la Piel/patología , Neoplasias Cutáneas/patología , Trasplante de Piel/patología , Antígenos Thy-1RESUMEN
Murine interleukin-4 (IL-4) exhibits potent antitumor activity when present at the site of tumor cell challenge. Associated with tumor cell death is the appearance of an inflammatory infiltrate comprised predominantly of eosinophils and macrophages, but with few lymphocytes. Antibodies that specifically block the accumulation of granulocytes at the site of inflammation were injected in vivo to define the cell type responsible for the antitumor action of IL-4. These studies implicate eosinophils in IL-4-mediated tumor cytotoxicity. The lymphoid-independent nature of IL-4 action is supported by the analysis of mutant mouse strains with defined lymphocyte immunodeficiencies. The observed regression of established tumor masses by localized IL-4 action provides a rationale for exploring IL-4-mediated tumor killing as a potential therapy for human malignant disorders.
Asunto(s)
Interleucina-4/uso terapéutico , Neutrófilos/fisiología , Plasmacitoma/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Cromatografía de Afinidad , Granulocitos/efectos de los fármacos , Granulocitos/patología , Inflamación , Interleucina-4/genética , Interleucina-4/aislamiento & purificación , Ratones , Ratones Endogámicos BALB C , Infecciones por Nematodos/sangre , Infecciones por Nematodos/patología , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Nippostrongylus , Plasmacitoma/patología , Plasmacitoma/terapia , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/uso terapéutico , TransfecciónAsunto(s)
Bioensayo/métodos , Factores Inmunológicos/uso terapéutico , Interleucina-4/uso terapéutico , Trasplante de Neoplasias , Células Tumorales Cultivadas/trasplante , Animales , Citocinas/administración & dosificación , Citocinas/uso terapéutico , Vectores Genéticos , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/genética , Memoria Inmunológica , Interleucina-4/administración & dosificación , Interleucina-4/genética , Subgrupos Linfocitarios/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Transfección , Trasplante HeterólogoRESUMEN
We have analyzed mice expressing IL-4 as a transgene, and found that expression of this lymphokine has profound effects on B cell function. B cells from transgenic mice exhibit phenotypic changes, including an increase in size and elevated expression of class II MHC. IL-4 increases the quantity of IgE produced by transgenic-derived B cells in response to LPS stimulation. In vivo, IL-4 markedly affects the serum Ig isotype repertoire. Serum levels of IgG1 and IgE are elevated, and levels of IgG2a, IgG2b, and IgG3 are depressed in IL-4 transgenic mice. Ag-specific antibody responses to immunization with hapten-carrier conjugates are also affected by IL-4. Transgenic mice show increased anti-hapten IgE and IgG1 and reduced anti-hapten IgG2a, IgG2b, and IgG3, compared with wild-type mice. Ag-specific IgE is substantially induced by T cell-dependent Ag, but not T cell-independent Ag, suggesting that cognate T-B interactions in addition to IL-4 are required for generating IgE responses in vivo. In vivo treatment with the anti-IL-4 mAb 11B11 reverses many of the isotype alterations in the transgenic mice, indicating that these changes arise as a direct consequence of IL-4 secretion.