RESUMEN
Cluster of differentiation (CD)8(+) T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8(+) T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1(-/-)) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.
Asunto(s)
Virus de la Coriomeningitis Linfocítica/fisiología , Especies Reactivas de Oxígeno/metabolismo , Animales , Butionina Sulfoximina/farmacología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Glutatión/metabolismo , Hígado/metabolismo , Coriomeningitis Linfocítica/patología , Coriomeningitis Linfocítica/prevención & control , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/deficiencia , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Bazo/metabolismoRESUMEN
To investigate the dependence of individual immunological processes on DC, a transgenic mouse system (CD11c-DTR/GFP mice) has been developed that allows conditional depletion of CD11c+ DC in vivo through administration of diphtheria toxin. We have performed careful histological analysis of CD11c-DTR/GFP mice at different time points after diphtheria toxin injection and confirmed the transient depletion of CD11c+ cells from lymph nodes and spleen. Unexpectedly, the injection of diphtheria toxin completely depleted marginal zone and metallophilic M(Phi) from the spleen and their sinusoidal counterparts from the lymph nodes. This finding limits the use of CD11c-DTR/GFP mice for the analysis of the role of DC to models and read outs that are proven to be independent of marginal zone and sinusoidal M(Phi).
Asunto(s)
Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Tejido Linfoide/inmunología , Macrófagos/inmunología , Receptores de Superficie Celular , Animales , Antimetabolitos/administración & dosificación , Recuento de Células , Ácido Clodrónico/administración & dosificación , Toxina Diftérica/administración & dosificación , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina , Inmunohistoquímica/métodos , Péptidos y Proteínas de Señalización Intercelular , Liposomas , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Fluorescente , Modelos Animales , Fagocitosis , Bazo/inmunologíaRESUMEN
Resistance of vertebrate hosts against infections comprises important natural or innate resistance combined with adaptive immune responses of T and B cells. Viruses, bacteria or classical parasites all probe the limit of immune responses and of immunity. They, therefore, offer an excellent opportunity to assess the biology, physiology and molecular aspects of immune responses and help in characterizing the three basic parameters of immunology-- specificity, tolerance and memory. Various experiments are summarized that indicate that the rules of antiviral, antitumour, antiorgan graft and of autoimmune responses are basically the same. The practical specificity repertoire of T and B cells is probably in the order of 10(4)-10(5) specificities expressed by T cells or by neutralizing antibodies. Tolerance is best defined by rules of reactivity to eliminate infections while avoiding destruction of normal cells by complete elimination of T cells that are specific for antigens persisting within the blood and lymphatic (lymphohaemopoietic) system. Induction of a T-cell response is the result of antigens newly entering lymph nodes or spleen, initially in a local fashion and exhibiting an optimal distribution kinetics within the lymphohaemopoietic system. Antigen staying outside lymphatic tissues are immunologically ignored (e.g. are non-events). Thus immune reactivity is regulated by antigen dose, time and relative distribution kinetics. Memory is the fact that a host is resistant against disease caused by reinfection with the same agent. Memory correlates best with antigen-dependent maintenance of elevated antibody titres in serum and mucosal secretions, or with an antigen-driven activation of T cells, such that they are protective immediately against peripheral reinfections in solid tissues. While antibodies transferred from mother to offspring are a prerequisite for the survival of otherwise unprotected immuno-incompetent offsprings, activated memory T cells cannot be transmitted. Thus, attenuation of infections in newborns and babies by maternal antibodies is the physiological correlate of man-made vaccines. T cells not only play an essential role in maintaining T-help-dependent memory antibody titres, but also in controlling the many infections that persist in a host at rather low levels (such as tuberculosis, measles and HIV).
Asunto(s)
Enfermedades Transmisibles/inmunología , Vacunas/inmunología , Linfocitos B/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Inmunidad Celular/inmunología , Memoria Inmunológica , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Linfocitos T/inmunologíaRESUMEN
Subclinical autoimmune responses can be frequently detected in healthy individuals. Sustained activation of autoreactive lymphocytes is, however, required for the development of autoimmune diseases associated with ongoing tissue destruction either in single organs or generalized with multiple manifestations. Clinical and experimental evidence suggests that prolonged presentation of self antigens by dendritic cells is crucial for the development of destructive autoimmune disease. We discuss here a simplified threshold model where the key parameters for the magnitude of the autoimmune response are the amount of previously ignored self peptides presented by dendritic cells and the duration of the antigen presentation in secondary lymphoid organs. Multiple factors influence the threshold for the conversion of an autoimmune response to overt autoimmune disease. Frequent or persistent viral infections of the target organ may favor autoimmune disease by increasing the amounts of released self antigens, generating cytokine-mediated bystander activation of self-reactive lymphocytes and/or sustaining a chronic response via neoformation of lymphoid structures in the target organ.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Células Dendríticas/inmunología , Animales , Presentación de Antígeno , Autoantígenos/metabolismo , Autoinmunidad , Humanos , Inflamación/inmunología , Ratones , Modelos Inmunológicos , Linfocitos T/inmunologíaAsunto(s)
Anticuerpos Antivirales/inmunología , Receptores Fc/inmunología , Acrecentamiento Dependiente de Anticuerpo , Reacciones Antígeno-Anticuerpo/inmunología , Antígenos Virales/ultraestructura , Linfocitos B/inmunología , Proteínas del Sistema Complemento/inmunología , Humanos , Memoria Inmunológica , Cooperación Linfocítica , Linfocitos T/inmunología , Vacunas/inmunología , Virosis/inmunología , Virus/inmunologíaRESUMEN
BACKGROUND: Leflunomide is an isoxazol derivative with immunosuppressive capacities in various experimental allo- and xenotransplantation models. Two main mechanisms of action have been described: Inhibition of pyrimidine de novo synthesis and impairment of tyrosine phosphorylation of different tyrosine kinases involved in receptor signaling via B cell and cytokine receptors. MATERIALS AND METHODS: Interference of Leflunomide with the IgM antibody responses to vesicular stomatitis virus (VSV, T-independent type 1), IgM to recombinant VSV glycoprotein (T-independent type 2), and IgG to lymphocytic choriomeningitis virus (LCMV, T-dependent) were analyzed whereas the cytotoxic T cell (CTL) response was examined after LCMV infection. Interference with the CD8+ T cell-mediated autoimmune diabetes in a transgenic mouse expressing the LCMV-glycoprotein in the pancreatic islets was studied as a model for T cell-mediated autoimmune diseases. Uridine substitution experiments were performed to differentiate between the above mentioned two mechanisms of action on different functions of the immune system in vivo. RESULTS: Leflunomide at 35 mg/kg/day suppressed the humoral immune response against all antigens tested. Similar effects on T-independent compared to T-dependent antibody responses required two to four times higher drug doses. CTL responses to LCMV were considerably impaired. Uridine substitution prevented lethal VSV encephalitis under Leflunomide treatment by restoring the neutralizing IgM and IgG responses. However, the inhibition of LCMV specific CTLs and suppression of CD8+ T cell-mediated autoimmune diabetes remained unaffected by additional uridine treatment. CONCLUSIONS: Leflunomide-mediated suppression of B cell and T helper cell activity but not of CTLs largely depends on inhibition of pyrimidine de novo synthesis.
Asunto(s)
Anticuerpos Antivirales/análisis , Inmunosupresores/farmacología , Isoxazoles/farmacología , Linfocitos T/efectos de los fármacos , Linfocitos T/fisiología , Uridina/farmacología , Animales , Formación de Anticuerpos/efectos de los fármacos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/prevención & control , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus/inmunología , Diabetes Mellitus/prevención & control , Relación Dosis-Respuesta a Droga , Leflunamida , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos/genética , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/fisiología , Virus de la Estomatitis Vesicular Indiana/inmunologíaRESUMEN
Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are initiated by extracerebral exposure to prions. Although prion transmission from extracerebral sites to the brain represents a potential target for prophylaxis, attempts at vaccination have been limited by the poor immunogenicity of prion proteins. To circumvent this, we expressed an anti-prion protein (anti-PrP) mu chain in Prnp(o/o) mice. Transgenic mice developed sustained anti-PrP titers, which were not suppressed by introduction of Prnp+ alleles. Transgene expression prevented pathogenesis of prions introduced by intraperitoneal injection in the spleen and brain. Expression of endogenous PrP (PrP(C)) in the spleen and brain was unaffected, suggesting that immunity was responsible for protection. This indicates the feasibility of immunological inhibition of prion disease in vivo.
Asunto(s)
Anticuerpos/inmunología , Proteínas PrPSc/inmunología , Priones/inmunología , Scrapie/prevención & control , Amiloide/genética , Animales , Anticuerpos/sangre , Linfocitos B/inmunología , Western Blotting , Química Encefálica , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Cadenas mu de Inmunoglobulina/sangre , Cadenas mu de Inmunoglobulina/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas PrPC/genética , Proteínas PrPSc/análisis , Proteínas Priónicas , Priones/genética , Precursores de Proteínas/genética , Bazo/química , Bazo/inmunologíaRESUMEN
Mutations in viral genomes that affect T-cell-receptor recognition by CD8+ cytotoxic T lymphocytes have been shown to allow viral evasion from immune surveillance during persistent viral infections. Although CD4+ T-helper cells are crucially involved in the maintenance of effective cytotoxic T-lymphocyte and neutralizing-antibody responses, their role in viral clearance and therefore in imposing similar selective pressures on the virus is unclear. We show here that transgenic virus-specific CD4+ Tcells, transferred into mice persistently infected with lymphocytic choriomeningitis virus, select for T-helper epitope mutant viruses that are not recognized. Together with the observed antigenic variation of the same T-helper epitope during polyclonal CD4+ T-cell responses in infected pore-forming protein-deficient C57BL/6 mice, this finding indicates that viral escape from CD4+ T lymphocytes is a possible mechanism of virus persistence.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Epítopos/inmunología , Virus ARN/fisiología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , ADN , Epítopos/química , Fusión de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Pruebas de NeutralizaciónRESUMEN
How, why, and when specific T and B lymphocytes respond against infection follow explicit rules, but how this can be assessed experimentally depends crucially on the methodology used. In this Viewpoint, we discuss the parameters of receptor specificity and antigen that determine whether an immune response can be accurately measured against model antigens and how this relates to protection against a given pathogen. We suggest that antigen structure, localization, dose, and time during which antigen is available are all decisive factors in regulating an immune response.
Asunto(s)
Antígenos/inmunología , Inmunidad , Animales , Linfocitos B/inmunología , Humanos , Infecciones/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T/inmunologíaRESUMEN
In addition to CD8+ cytotoxic T lymphocyte (CTL) responses, neutralizing antibodies contribute substantially to the long-term immune control of noncytopathic viruses, as demonstrated during infection with the lymphocytic choriomeningitis virus (LCMV). The high virus load during the initial phase of an infection and the ability of this RNA virus to spontaneously acquire mutations are important prerequisites for escaping an ongoing immune response. In this context, LCMV escape from the humoral response by single point mutations in neutralizing envelope protein determinants may occur, particularly during conditions of CTL deficiency, leading to virus persistence.
Asunto(s)
Anticuerpos Antivirales/inmunología , Antígenos Virales , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas Virales , Animales , Antígenos CD8/genética , Antígenos CD8/inmunología , Reacciones Cruzadas , Evolución Molecular Dirigida , Variación Genética , Glicoproteínas/genética , Glicoproteínas/inmunología , Humanos , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/genética , Ratones , Ratones Noqueados , Modelos Inmunológicos , Pruebas de Neutralización , Mutación Puntual , Linfocitos T Citotóxicos/inmunologíaRESUMEN
We investigated here the effects of perforin on CTL responses during interaction of dendritic cells (DC) with cytotoxic T lymphocytes in vivo. Using MHC class I tetramers complexed with the immunodominant CTL epitope of the lymphocytic choriomeningitis virus glycoprotein (LCMV-GP33), we followed the kinetics of DC-induced CTL responses. GP33-presenting DC induced rapid primary expansion of both perforin-competent and -deficient CTL with similar kinetics. Secondary CTL responses in perforin-deficient and normal control mice after DC-booster immunization were more rapid than the primary responses, but never reached the high initial levels, suggesting that reactivated memory CTL eliminated the antigen-presenting DC and thereby limited the booster effect. Whereas killingof DC in vitro was strictly dependent on perforin, elimination of GP33-presenting DC by CTL in vivo was largely independent of perforin and Fas. Taken together, these results suggest that control of DC homeostasis by CTL, i. e. elimination of DC by the effector cells they had elicited, is controlled via multiple and probably redundant signals and represents an important fail-safe mechanism to avoid exaggerated CTL responses.
Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia Adoptiva , Glicoproteínas de Membrana/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos Virales/inmunología , Femenino , Glicoproteínas/inmunología , Homeostasis , Cinética , Activación de Linfocitos/inmunología , Masculino , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fragmentos de Péptidos/inmunología , Perforina , Proteínas Citotóxicas Formadoras de Poros , Proteínas Virales/inmunologíaRESUMEN
Surface, membrane-bound, immunoglobulin M (IgM) or IgD expression early in B cell ontogeny is considered essential for the differentiation of antibody-producing cells in mammals; only in IgM+ B cells is the heavy chain locus rearranged to express antibodies of other classes. We show here that IgA is selectively expressed in muMT mice, which lack IgM or IgD expression and have a pro-B cell developmental block. muMT IgA binds proteins of commensal intestinal bacteria and is weakly induced by Salmonella infection, although not through conventional immunization. This muMT IgA pathway requires extrasplenic peripheral lymphoid tissues and may be an evolutionarily primitive system in which immature B cells switch to IgA production at peripheral sites.
Asunto(s)
Linfocitos B/inmunología , Inmunoglobulina A/biosíntesis , Cadenas delta de Inmunoglobulina/inmunología , Cadenas mu de Inmunoglobulina/inmunología , Animales , Inmunoglobulina A/sangre , Inmunoglobulina D/análisis , Cadenas delta de Inmunoglobulina/genética , Cadenas mu de Inmunoglobulina/genética , Mucosa Intestinal/inmunología , Tejido Linfoide/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Bazo/inmunologíaRESUMEN
The vertebrate immune system has evolved to protect against infections that threaten survival before reproduction. Clinically manifest tumours mostly arise after the reproductive years and somatic mutations allow even otherwise antigenic tumours to evade the attention of the immune system. Moreover, the lack of immunological co-stimulatory molecules on solid tumours could result in T-cell tolerance; that is, the failure of T cells to respond. However, this may not generally apply. Here we report several important findings regarding the immune response to tumours, on the basis of studies of several tumour types. First, tumour-specific induction of protective cytotoxic T cells (CTLs) depends on sufficient tumour cells reaching secondary lymphatic organs early and for a long enough duration. Second, diffusely invading systemic tumours delete CTLs. Third, tumours that stay strictly outside secondary lymphatic organs, or that are within these organs but separated from T cells by barriers, are ignored by T cells but do not delete them. Fourth, co-stimulatory molecules on tumour cells do not influence CTL priming but enhance primed CTL responses in peripheral solid tumours. Last, cross priming of CTLs by tumour antigens, mediated by major histocompatibility complex (MHC) class I molecules of antigen-presenting host cells, is inefficient and not protective. These rules of T-cell induction and maintenance not only change previous views but also rationales for anti-tumour immunotherapy.
Asunto(s)
Vigilancia Inmunológica , Metástasis Linfática/inmunología , Tejido Linfoide/inmunología , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Antígeno B7-1/inmunología , Antígenos CD28/inmunología , Glicoproteínas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Ganglios Linfáticos/inmunología , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Transducción de Señal , Transfección , Células Tumorales Cultivadas , Escape del Tumor/inmunologíaRESUMEN
New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.
Asunto(s)
Proteínas del Sistema Complemento/metabolismo , Enfermedades por Prión/etiología , Enfermedades por Prión/inmunología , Animales , Secuencia de Bases , Encéfalo/metabolismo , Encéfalo/patología , Proteínas del Sistema Complemento/deficiencia , Proteínas del Sistema Complemento/genética , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Enfermedades por Prión/patología , Priones/metabolismo , Receptores de Complemento/deficiencia , Receptores de Complemento/genética , Receptores de Complemento/metabolismo , Scrapie/etiología , Scrapie/inmunología , Scrapie/patología , Bazo/inmunología , Bazo/metabolismo , Factores de TiempoAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/inmunología , Coriomeningitis Linfocítica/terapia , Linfocitos T Citotóxicos/inmunología , Animales , Modelos Animales de Enfermedad , Inmunización Pasiva , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , RatonesRESUMEN
This study evaluated to what extent presentation of exogenously acquired self-Ags via MHC class I molecules on DC might contribute to the activation of self-reactive CTL and subsequent development of autoimmune disease. We show here by using the rat insulin promotor lymphocytic choriomeningitis virus glycoprotein model of autoimmune diabetes that the activation of self-reactive CTL by DC after uptake of exogenous Ag is very limited, first by the short half-life of MHC class I-associated peptides on DC in vitro and in vivo, and second by the rather inefficient MHC class I presentation of cell-associated self-Ags by DC. These two mechanisms are probably crucial in establishing high thresholds for the induction of self-reactive CTL that prevent autoimmune sequelae after release of sequestered and previously immunologically ignored tissue Ags.
Asunto(s)
Presentación de Antígeno , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Células Dendríticas/inmunología , Activación de Linfocitos , Péptidos/inmunología , Péptidos/metabolismo , Linfocitos T Citotóxicos/inmunología , Proteínas Virales , Secuencia de Aminoácidos , Animales , Presentación de Antígeno/genética , Antígenos Virales/genética , Citotoxicidad Inmunológica/genética , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/patología , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Inyecciones Subcutáneas , Insulina/genética , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Activación de Linfocitos/genética , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Regiones Promotoras Genéticas/genética , Regiones Promotoras Genéticas/inmunología , Ratas , Linfocitos T Colaboradores-Inductores/inmunología , Células Tumorales Cultivadas/trasplanteRESUMEN
Although DNA vaccines have been shown to elicit potent immune responses in animal models, initial clinical trials in humans have been disappointing, highlighting a need to optimize their immunogenicity. Naked DNA vaccines are usually administered either i.m. or intradermally. The current study shows that immunization with naked DNA by direct injection into a peripheral lymph node enhances immunogenicity by 100- to 1,000-fold, inducing strong and biologically relevant CD8(+) cytotoxic T lymphocyte responses. Because injection directly into a lymph node is a rapid and easy procedure in humans, these results have important clinical implications for DNA vaccination.
Asunto(s)
Antígenos Virales/genética , ADN Viral/inmunología , Glicoproteínas/genética , Virus de la Coriomeningitis Linfocítica/genética , Fragmentos de Péptidos/genética , Vacunas de ADN/administración & dosificación , Proteínas Virales/genética , Vacunas Virales/administración & dosificación , Animales , Línea Celular , Epítopos de Linfocito T/genética , Proteínas de Homeodominio/genética , Epítopos Inmunodominantes/genética , Inyecciones Intralinfáticas/métodos , Coriomeningitis Linfocítica/prevención & control , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plásmidos/inmunología , Linfocitos T Citotóxicos/inmunología , Vacunación , Vacunas de ADN/inmunología , Vacunas Virales/inmunologíaRESUMEN
The immune system has to be optimally balanced to be highly effective against infections with cytopathic microbial pathogens and must guarantee efficient destruction of cells infected with noncytopathic agents while leaving the integrity of noninfected cells largely unaltered. We describe here the effects of genetically induced hypercholesterolemia on cellular immunity in apolipoprotein E (ApoE(-/-)) and low density lipoprotein receptor-deficient (LDLR(-/-)) mice during infection with the hepatotropic lymphocytic choriomeningitis virus WE strain. In both ApoE(-/-) and LDLR(-/-) mice hypercholesterolemia aggravated virus-induced immunopathologic liver disease. ApoE(-/-) mice exhibited a higher susceptibility to virus-induced immunopathology than LDLR(-/-) mice and usually succumbed to immunopathologic disease when infected with high doses of virus. Initial virus spread was not influenced by the hypercholesterolemia, whereas clearance of the virus from spleen and nonlymphoid organs, including liver, was delayed. Activation of antiviral CTL, measured by ex vivo cytotoxicity and IFN-gamma production, and recruitment of specific CTL into blood and liver were impaired in hypercholesterolemic mice, indicating that hypercholesterolemia had a significant suppressive effect on cellular immunity. Taken together, these data provide evidence that hypercholesterolemia suppresses antiviral immune responses, thereby changing the host-virus balance, and can increase susceptibility to acute or chronic and potentially lethal virus-induced immunopathologic disease. These findings impinge on our understanding of hypercholesterolemia as a disease parameter and may explain aspects of the frequent association of persistent pathogens with hypercholesterolemia-induced diseases, such as atherosclerosis.