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1.
Immunity ; 29(5): 782-94, 2008 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-19006695

RESUMEN

Chronic viral infections of the hematopoietic system are associated with bone marrow dysfunction, to which both virus-mediated and immune-mediated effects may contribute. Using unresolving noncytopathic Friend virus (FV) infection in mice, we showed that unregulated CD4(+) T cell response to FV caused IFN-gamma-mediated bone marrow pathology and anemia. Importantly, bone marrow pathology was triggered by relative insufficiency in regulatory T (Treg) cells and was prevented by added Treg cells, which suppressed the local IFN-gamma production by FV-specific CD4(+) T cells. We further showed that the T cell receptor (TCR) repertoire of transgenic Treg cells expressing the beta chain of an FV-specific TCR was virtually devoid of FV-specific clones. Moreover, anemia induction by virus-specific CD4(+) T cells was efficiently suppressed by virus-nonspecific Treg cells. Thus, sufficient numbers of polyclonal Treg cells may provide substantial protection against bone marrow pathology in chronic viral infections.


Asunto(s)
Anemia/inmunología , Médula Ósea/inmunología , Médula Ósea/fisiopatología , Linfocitos T CD4-Positivos/inmunología , Virus de la Leucemia Murina de Friend/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Infecciones por Retroviridae/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Anemia/metabolismo , Anemia/virología , Animales , Médula Ósea/patología , Linfocitos T CD4-Positivos/metabolismo , Enfermedad Crónica , Virus de la Leucemia Murina de Friend/patogenicidad , Técnicas de Silenciamiento del Gen , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Infecciones por Retroviridae/patología , Infecciones por Retroviridae/fisiopatología , Infecciones por Retroviridae/virología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo
2.
Heart Vessels ; 30(1): 126-35, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24493328

RESUMEN

The in vivo mechanisms in chronic myocarditis remain unclear. The aim of the current study was to clarify the genomic difference of amyocarditic (CB3O) and myocarditic (CB3M) coxsackievirus B3 (CB3) and the pathogenesis of in vivo mechanisms in chronic myocarditis. We examined the histopathology of CB3-inoculated wild-type (WT) and severe combined immunodeficient (SCID) mice with and without adoptive transfer of lymphocytes. There were no differences in viral growth between CB3O and CB3M. There were four to six nucleotide differences in the sequence of CB3O in comparison with the known CB3M. The difference in virus sequence between CB3O and CB3M was very minimal. The changes were located in 1A, 1C, and 1D regions, which encode the structural capsid proteins. Definite myocarditis developed in WT C3H (H-2(k)) inoculated with CB3M. On the contrary, trivial or mild myocarditis occurred in WT C3H mice inoculated with CB3O. In SCID C3H and SCID C57BL/6 (H-2(b)) mice, definite myocarditis developed by inoculation with both CB3O and CB3M. Myocardial lesion was less severe in the mice infected with CB3O than in those with CB3M. After anti-CD8 antibody treatment, myocarditis was easily induced in mice originally showing resistance to infection. In addition, chronic myocarditis developed in CB3O-infected SCID C3H mice reconstituted with CB3M-sensitized splenocytes of WT C3H mice. The development of chronic myocarditis primarily depends on the presence or absence of the virus genome, and secondarily on the complex interaction between virus virulence and immunological background of the host. CB3 infection may cause chronic myocarditis with ongoing inflammation with or without viral persistence.


Asunto(s)
Infecciones por Coxsackievirus/terapia , Enterovirus/genética , Miocarditis/mortalidad , Miocarditis/virología , Miocardio/patología , Traslado Adoptivo/veterinaria , Animales , Anticuerpos Monoclonales/química , Linfocitos T CD8-positivos/citología , Enfermedad Crónica , Genoma Viral , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones SCID , Necrosis/patología , Nucleótidos/clasificación
3.
Toxicol Appl Pharmacol ; 273(1): 10-8, 2013 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-24035973

RESUMEN

In the past few decades, there has been a significant increase in incidence of allergic diseases. The hygiene hypothesis may provide some clues to explain this rising trend, but it may also be attributable to other environmental factors that exert a proallergic adjuvant effects. However, there is limited information on the risks of developing allergic asthma and related diseases through the ingestion of environmental chemicals found in food contaminants. In the present study, we have shown that oral administration of tributyltin, used as a model environmental chemical, induced oxidative-stress status in the bronchial lymph node, mesenteric lymph node and spleen, but not in the lung, where the initial step of allergic asthma pathogenesis takes place. Mice exposed to tributyltin exhibited heightened Th2 immunity to the allergen with more severe airway inflammation. Tributyltin also induced Treg cells apoptosis preferentially over non-Treg cells. All these effects of tributyltin exposure were canceled by the administration of glutathione monoethyl ester. Meanwhile, tributyltin did not affect airway inflammation of mice transferred with allergen-specific Th2 cells. Collectively, these results suggest that tributyltin exerts its pathological effect during the sensitization phase through oxidative stress that enhances the development of allergic diseases. The current study dissects the pathogenic role of oxidative stress induced by oral exposure to an environmental chemical during the sensitization phase of allergic airway inflammation and would be important for developing therapeutics for prevention of allergic diseases.


Asunto(s)
Hiperreactividad Bronquial/patología , Disruptores Endocrinos/toxicidad , Contaminación de Alimentos/análisis , Inflamación/patología , Estrés Oxidativo/efectos de los fármacos , Alérgenos/efectos adversos , Animales , Apoptosis/efectos de los fármacos , Asma/inducido químicamente , Asma/patología , Hiperreactividad Bronquial/inducido químicamente , Diferenciación Celular , Glutatión/análogos & derivados , Glutatión/farmacología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/patología , Células Th2/efectos de los fármacos , Células Th2/patología , Compuestos de Trialquiltina/efectos adversos , Compuestos de Trialquiltina/sangre
4.
Int J Cancer ; 129(5): 1126-36, 2011 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21710495

RESUMEN

We previously showed that exposure to UV radiation after immunization suppresses Th1 and Th2 immune responses, leading to impaired Ab and allo-immune responses, but the impact of UV radiation after immunization on anti-tumor immune responses mediated by tumor-specific CD8(+) T cell responses remains less clear. Furthermore, the exact phenotypic and functional characteristics of regulatory T cell population responsible for the UV-induced immunosuppression still remain elusive. Using the MBL-2 lymphoma cell line engineered to express OVA as a surrogate tumor Ag, here we demonstrate that UV irradiation after tumor Ag-immunization suppresses the anti-tumor immune response in a manner dependent on the immunizing Ag. This suppression was mediated by interleukin (IL)-10 released from CD4(+) CD25(+) T cells, by which impaired the induction of cytotoxic T lymphocytes (CTL) able to kill Ag-expressing tumor cells. In addition, we generated a panel of T cell clones from UV-irradiated and non-irradiated mice, and all of the clones derived from UV-irradiated mice had a Tr1-type regulatory T cell phenotype with expression of IL-10 and c-Maf, but not Foxp3. These Tr1-type regulatory T cell clones suppressed tumor rejection in vivo as well as Th cell activation in vitro in an IL-10 dependent manner. Given that suppression of Ag-specific CTL responses can be induced in Ag-sensitized mice by UV irradiation, our results may imply that exposure to UV radiation during premalignant stage induces tumor-Ag specific Tr1 cells that mediate tumor-Ag specific immune suppression resulting in the promotion of tumor progression.


Asunto(s)
Interleucina-10/metabolismo , Linfoma/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de la radiación , Células TH1/inmunología , Células Th2/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/efectos de la radiación , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de la radiación , Ensayo de Inmunoadsorción Enzimática , Femenino , Tolerancia Inmunológica , Inmunización , Terapia de Inmunosupresión , Activación de Linfocitos , Linfoma/metabolismo , Linfoma/patología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Proteínas Proto-Oncogénicas c-maf/metabolismo , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/efectos de la radiación , Células Th2/efectos de la radiación
5.
J Exp Med ; 201(5): 681-6, 2005 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-15753203

RESUMEN

The antigenic targets recognized by naturally occurring CD4(+) CD25(+) regulatory T cells (T reg cells) have been elusive. We have serologically defined a series of broadly expressed self-antigens derived from chemically induced mouse sarcomas by serological identification of antigens by recombinant expression cloning (SEREX). CD4(+) CD25(+) T cells from mice immunized with SEREX-defined self-antigens had strong suppressive activity on peptide-specific proliferation of CD4(+) CD25(-) T cells and CD8(+) T cells. The suppressive effect was observed without in vitro T cell stimulation. Foxp3 expression in these CD4(+) CD25(+) T cells from immunized mice was 5-10 times greater than CD4(+) CD25(+) T cells derived from naive mice. The suppressive effect required cellular contact and was blocked by anti-glucocorticoid-induced tumor necrosis factor receptor family-related gene antibody. In vitro suppressive activity essentially disappeared 8 wk after the last immunization. However, it was regained by in vitro restimulation with cognate self-antigen protein but not with control protein. We propose that SEREX-defined self-antigens such as those used in this study represent self-antigens that elicit naturally occurring CD4(+) CD25(+) T reg cells.


Asunto(s)
Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Receptores de Interleucina-2/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/genética , Femenino , Factores de Transcripción Forkhead , Regulación de la Expresión Génica , Tolerancia Inmunológica , Inmunización , Activación de Linfocitos , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo
6.
Eur J Immunol ; 40(3): 787-96, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20017193

RESUMEN

Oxidative stress plays an important role in the pathogenesis of asthma via the upregulation of local inflammatory mediators and/or promoting Th2-skewing during Ag sensitization. Thioredoxin (TRX), a 12 kDa redox-active protein with antioxidative property, has been recently shown to play a protective role in various inflammatory diseases. Using a mouse model of asthma, we show here that IL-13 and eotaxin production are decreased in TRX-Tg mice leading to reduced eosinophils recruitment and mucus metaplasia. The reduction in airway inflammation occurs without the attenuation of systemic Th2 immunity in that comparable levels of Th2-type cytokines and Ig were detected in LN and serum, respectively, from TRX-Tg and WT mice. Likewise, CD4(+) T cells from both strains of mice developed similar Th1 and Th2 responses in vitro. Asthmatic lungs of TRX-Tg and WT mice contained similar amounts of GATA-3(+) and Foxp3(+) T cells. Finally, production of MIF, an upstream modulator of airway inflammation, was significantly reduced in the lungs of TRX-Tg mice. Our data suggest that TRX suppresses airway inflammation by inhibiting MIF production thereby limiting the downstream recruitment of eosinophils to the lung independently of modulating systemic Th1/Th2 immunity.


Asunto(s)
Asma/inmunología , Neumonía/inmunología , Células TH1/inmunología , Células Th2/inmunología , Tiorredoxinas/inmunología , Animales , Asma/metabolismo , Diferenciación Celular/inmunología , Quimiotaxis de Leucocito/inmunología , Ensayo de Inmunoadsorción Enzimática , Eosinófilos/inmunología , Humanos , Interleucina-13/biosíntesis , Interleucina-13/metabolismo , Oxidorreductasas Intramoleculares/inmunología , Factores Inhibidores de la Migración de Macrófagos/inmunología , Ratones , Ratones Transgénicos , Neumonía/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/citología , Células Th2/citología
7.
J Immunol ; 181(10): 6889-97, 2008 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-18981108

RESUMEN

Although CD4(+)CD25(+) regulatory T (Treg) cells are known to suppress Th1 cell-mediated immune responses, their effect on Th2-type immune responses remains unclear. In this study we examined the role of Treg cells in Th2-type airway inflammation in mice. Depletion and reconstitution experiments demonstrated that the Treg cells of naive mice effectively suppressed the initiation and development of Th2-driven airway inflammation. Despite effective suppression of Th2-type airway inflammation in naive mice, adoptively transferred, allergen-specific Treg cells were unable to suppress airway inflammation in allergen-presensitized mice. Preactivated allergen-specific Treg cells, however, could suppress airway inflammation even in allergen-presensitized mice by accumulating in the lung, where they reduced the accumulation and proliferation of Th2 cells. Upon activation, allergen-specific Treg cells up-regulated CCR4, exhibited enhanced chemotactic responses to CCR4 ligands, and suppressed the proliferation of and cytokine production by polarized Th2 cells. Collectively, these results demonstrated that Treg cells are capable of suppressing Th2-driven airway inflammation even in allergen-presensitized mice in a manner dependent on their efficient migration into the inflammatory site and their regulation of Th2 cell activation and proliferation.


Asunto(s)
Neumonía/inmunología , Linfocitos T Reguladores/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Proliferación Celular , Citocinas/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Ovalbúmina/inmunología , Neumonía/inducido químicamente
8.
Int Immunol ; 20(1): 57-70, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18006879

RESUMEN

It is well documented that UV radiation present in sunlight suppresses immune responses, especially T(h)1-driven cellular immune responses, resulting in the exacerbation of skin cancer and infectious diseases. However, the effects of UV irradiation on humoral immune responses remain less clearly defined. In addition, the majority of studies documenting immunosuppressive effects of UV irradiation has been demonstrated in animals exposed to UV radiation before immunization. In the present study, therefore, we examined the effects of UV irradiation on humoral immune responses in mice that had been immunized before UV irradiation. Both T(h)1- and T(h)2-associated Ig responses were significantly suppressed by UV irradiation given 7 days after immunization in an antigen-specific manner. Adoptive transfer experiments revealed that CD4(+) T cells from UV-irradiated mice are responsible for the UV-induced suppression of antibody responses. These CD4(+) regulatory T cells suppressed proliferation of conventional CD4(+) T cells in vivo and in vitro and contained IL-10-producing cells that did not express Foxp3. Mice depleted of CD25(+) cells also exhibited reduced antibody responses by UV irradiation. Finally, we showed that CD4(+) T cells from UV-irradiated mice treated with anti-IL-10 mAb failed to suppress antibody responses upon transfer. These results indicate that UV irradiation after immunization suppresses T(h)1- and T(h)2-mediated humoral immunity via the generation of Tr1-like regulatory T cells, in the process of which IL-10 appears to be important. Possible detrimental effects of UV irradiation after vaccination are also discussed.


Asunto(s)
Formación de Anticuerpos/efectos de la radiación , Antígenos/inmunología , Terapia de Inmunosupresión , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Formación de Anticuerpos/inmunología , Antígenos/administración & dosificación , Femenino , Inmunización , Interleucina-10/biosíntesis , Ratones , Ratones Endogámicos C57BL , Organismos Libres de Patógenos Específicos , Células TH1/inmunología , Células Th2/inmunología , Factores de Tiempo
9.
Biochem Pharmacol ; 75(2): 552-61, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-17977519

RESUMEN

Tributyltin (TBT), an environmental pollutant, debilitates immune responses via induction of apoptosis in CD4(+) T cells through an undefined mechanism of action. Accumulating evidence indicates that the susceptibility of Th1 and Th2 cells to TBT-induced apoptosis differs. In this study, by using HL-60 cell model, we show that hydrogen peroxide (H(2)O(2)) plays a critical role in TBT-induced apoptosis. Generation of H(2)O(2) induced by TBT resulted in a change in mitochondrial membrane potential that proceed apoptotic pathway where, at least in part, involved activation of caspase-3. We also demonstrated that Th1 clones appear to be more vulnerable to apoptosis induction than Th2 clones following exposure to TBT, which was well correlated with increased H(2)O(2) generation in Th1 clones than Th2 clones. There was an inverse correlation between TBT-induced apoptosis and the basal levels of intracellular GSH, a major cellular antioxidant. Furthermore, the addition of NAC that replenish intracellular GSH levels inhibited generation of H(2)O(2) and apoptosis in Th1 clones. These results suggest that TBT selectively induces apoptosis via generation of H(2)O(2) in Th1 cells because of their low GSH levels, which may contribute to the Th2 predominance induced by TBT.


Asunto(s)
Apoptosis/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Compuestos de Trialquiltina/toxicidad , Fragmentación del ADN/efectos de los fármacos , Glutatión/análisis , Células HL-60 , Humanos , Peróxido de Hidrógeno/metabolismo , Potenciales de la Membrana/efectos de los fármacos
10.
Transpl Immunol ; 19(1): 45-54, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18346637

RESUMEN

It is well documented that ultraviolet (UV) radiation present in sunlight suppresses immune responses. However, the majority of studies documenting the immunosuppressive effects of UV irradiation have been carried out in animals exposed to UV irradiation before immunization. Here, we report that recipient mice exposed to UV irradiation 7 days after immunization with a donor alloantigen exhibited prolongation of allograft survival in an alloantigen-specific manner. Recipient mice (H-2(b)) intravenously immunized with 2 x 10(7) allogeneic spleen cells (H-2(b/d)) 7 days before UV irradiation (40 kJ/m(2)) showed prolonged survival of allografts presenting the alloantigen used for sensitization (H-2(b/d)), but not third-party allografts (H-2(b/k)). Adoptive transfer experiments revealed that CD4(+) T cells in UV-irradiated recipients were responsible for this prolongation. CD4(+) T cells that could transfer the suppression produced large amounts of interleukin (IL)-10, but not IL-4. The effect of UV irradiation on alloantigen-specific immunosuppression was cancelled by administration of an anti-IL-10 monoclonal antibody. These results indicate that UV irradiation given after alloantigen immunization induces alloantigen-specific type 1 regulatory T cell-like regulatory T cells that prolong allograft survival and imply that the difficulties associated with predicting donor-related organ availability in transplantation can be dealt with, given the effectiveness of UV irradiation after immunization.


Asunto(s)
Supervivencia de Injerto/inmunología , Interleucina-10/inmunología , Isoantígenos/inmunología , Trasplante de Piel/inmunología , Linfocitos T Reguladores/metabolismo , Trasplante Homólogo/inmunología , Rayos Ultravioleta , Animales , Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Rechazo de Injerto/prevención & control , Inmunización , Terapia de Inmunosupresión , Ratones , Linfocitos T Reguladores/inmunología
11.
Int J Oncol ; 29(5): 1119-25, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17016642

RESUMEN

Monoclonal antibodies are finding ever increasing therapeutic applications. However, lethal liver damage has been reported following monoclonal antibody (mAb) treatment in combination with subtoxic doses of cytotoxic drugs. In this study, mice were intravenously injected with 200 microg/mouse of anti-CD8 (anti-Lyt-2.2), anti-CD4 (GK1.5) or anti-B220 (RA3-6B2) mAb. Subsequently, mice were administered 15 mg azoxymethane (AOM) per kg body weight by subcutaneous injection. Unexpectedly, all mice pretreated with mAb died within 72 h of a single injection of AOM. The injection of mAb-coated spleen cells accelerated the induction and the severity of liver disease. We found that mAb treatment activates Kupffer cells to produce inflammatory cytokines such as TNF-alpha and IL-12, and induces the expression of FasL on Kupffer and NKT cells. The concomitant upregulation of Fas on hepatocytes increases the susceptibility of the liver to apoptotic signals, and subsequent treatment with AOM causing mitochondrial injury synergistically induces lethal liver damage. Consistently, the lethal liver damage was abrogated in mice which were deficient for Kupffer cells, NKT cells or Fas-antigen. In conclusion, we have demonstrated a potential risk of lethal fulminant liver damage in the concomitant use of therapeutic antibodies and cytotoxic drugs. A possible side effect of antibody therapy is mediated through activation of the immune system, the very mechanism of action on which this treatment depends. In this context, the risk of combining therapeutic antibodies with other agents, particularly cytotoxic drugs, requires careful consideration.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Macrófagos del Hígado/efectos de los fármacos , Fallo Hepático Agudo/etiología , Hígado/efectos de los fármacos , Animales , Antígenos CD4/inmunología , Antígenos CD8/inmunología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Proteína Ligando Fas/análisis , Proteína Ligando Fas/genética , Inmunoglobulina M/administración & dosificación , Inmunoglobulina M/efectos adversos , Inyecciones Intravenosas , Interleucina-12/metabolismo , Células Asesinas Naturales/química , Macrófagos del Hígado/química , Macrófagos del Hígado/inmunología , Antígenos Comunes de Leucocito/inmunología , Hígado/patología , Fallo Hepático Agudo/patología , Ratones , Factor de Necrosis Tumoral alfa/metabolismo , Receptor fas/análisis , Receptor fas/genética , Receptor fas/metabolismo
12.
Circ Res ; 93(10): 948-56, 2003 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-14563711

RESUMEN

Several prospective clinical studies have indicated that hydroxymethylglutaryl-coenzyme A reductase inhibitors, statins, prevent cardiovascular events in part through their antiinflammatory properties. Because inflammation is positively and negatively regulated by T helper (Th) 1 cells and Th2 cells, respectively, we examined the effects of statins on the Th polarization in vitro and in vivo. Here we demonstrated that the statins tested, ie, cerivastatin, simvastatin, lovastatin, and atorvastatin, promoted Th2 polarization through both inhibition of Th1 development and augmentation of Th2 development of CD4+ T cells primed in vitro with anti-CD3 antibody and splenic antigen-presenting cells. Cerivastatin exerted most potent effect on modulation of Th1/Th2 development, and the effect was completely abrogated by an addition of mevalonate. Consistent with in vitro experiments, cerivastatin treatment decreased IFN-gamma production of lymph node cells from mice immunized with ovalbumin emulsified in complete Freund's adjuvant, indicating that Th1 development is also suppressed in an in vivo proinflammatory environment. In this murine model, cerivastatin significantly reduced mesangial matrix expansion of glomeruli in the kidney and attenuated proteinuria. The decrease of glomerular sclerosis by cerivastatin treatment was positively related to the suppression of interferon (IFN)-gamma-producing Th1 response in draining lymph node cells. Hence, these findings strongly suggest that statins' inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase regulates Th1/Th2 polarization in vivo and such a mechanism possibly plays a pathophysiological role in immune-related glomerular injury.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hidroximetilglutaril-CoA-Reductasas NADP-Dependientes/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Animales , Antígenos CD/biosíntesis , Apoptosis/efectos de los fármacos , Antígeno B7-1/biosíntesis , Antígeno B7-2 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Citocinas/biosíntesis , Inhibidores Enzimáticos/farmacología , Femenino , Antígenos de Histocompatibilidad Clase II/biosíntesis , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Piridinas/farmacología , Bazo/citología , Células TH1/inmunología , Células Th2/inmunología
13.
J Leukoc Biol ; 78(4): 921-9, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16037408

RESUMEN

Human Langerhans cells (LCs) are of hematopoietic origin, but cytokine regulation of their development is not fully understood. Notch ligand Delta-1 is expressed in a proportion of the skin. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) are also secreted in the skin. We report here that Delta-1, in concert with GM-CSF and TGF-beta1, induces the differentiation of human CD14(+) blood monocytes into cells that express LC markers: CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, E-cadherin, and Birbeck granules. The resulting cells display phagocytic activity and chemotaxis to macrophage inflammatory protein-1alpha (MIP-1alpha). In response to CD40 ligand and tumor necrosis factor alpha, the cells acquire a mature phenotype of dendritic cells that is characterized by up-regulation of human leukocyte antigen (HLA)-ABC, HLA-DR, CD80, CD86, CD40, and CD54 and appearance of CD83. These cells in turn show chemotaxis toward MIP-1beta and elicit activation of CD8(+) T cells and T helper cell type 1 polarization of CD4(+) T cells. Thus, blood monocytes can give rise to LCs upon exposure to the skin cytokine environment consisting of Delta-1, GM-CSF, and TGF-beta1, which may be, in part, relevant to the development of human epidermal LCs. Our results extend the functional scope of Notch ligand delta-1 in human hematopoiesis.


Asunto(s)
Células de Langerhans/citología , Células de Langerhans/fisiología , Receptores de Lipopolisacáridos/sangre , Proteínas de la Membrana/fisiología , Monocitos/citología , Monocitos/fisiología , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Polaridad Celular/fisiología , Células Cultivadas , Quimiotaxis/fisiología , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Proteínas de Homeodominio/efectos de los fármacos , Proteínas de Homeodominio/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular , Células de Langerhans/efectos de los fármacos , Ligandos , Receptores de Lipopolisacáridos/efectos de los fármacos , Receptores de Lipopolisacáridos/metabolismo , Proteínas de la Membrana/farmacología , Monocitos/efectos de los fármacos , Fenotipo , Factor de Transcripción HES-1 , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1
14.
Transpl Immunol ; 32(3): 156-63, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25861842

RESUMEN

Ultraviolet (UV) irradiation prior to antigen immunization is employed to induce antigen-specific regulatory T cells (Tregs). UV-induced Tregs demonstrate unique bystander suppression, although antigen-specific activation is required initially. We previously reported the phenotype of alloantigen-specific transferable Tregs induced by UV-B irradiation after immunization was the same as T regulatory type 1-like CD4(+) T cells, with antigen-specific interleukin (IL)-10 production. Here, by using semi-allogeneic transplantation models in vivo, we investigated the role of IL-10 in the induction and activation of these Tregs, and the possibility of bystander suppression of third-party allograft rejection. Naïve mice (H-2(b)) were immunized with alloantigen (H-2(b/d)), and received UV-B irradiation (40 kJ/m(2)) 1 week later. Four weeks afterwards, splenic CD4(+) T cells were purified from the UV-irradiated immunized mice, and were transferred into naïve mice (H-2(b)). Allografts expressing the same alloantigen as T-cell donors were immunized against (H-2(b/d)) or an irrelevant alloantigen (H-2(b/k)) were transplanted to CD4(+) T-cell-transferred mice, and an alloantigen-specific prolongation of allograft survival observed. Experiments where IL-10 was neutralized by monoclonal antibody in the induction or effector phase revealed that IL-10 is critical, not only for induction but also for immunosuppressive function of CD4(+) Tregs induced by UV irradiation after alloantigen immunization. Third-party allografts (H-2(d/k)) were transplanted to CD4(+) T-cell-transferred mice, and graft survival was also prolonged. Even a graft only partially compatible with immunized alloantigen worked well in vivo to activate CD4(+) Tregs induced by UV irradiation after alloantigen immunization, which resulted in the bystander suppression of third-party allograft rejection.


Asunto(s)
Rechazo de Injerto/inmunología , Trasplante de Corazón , Interleucina-10/metabolismo , Trasplante de Piel , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Comunicación Celular , Femenino , Rechazo de Injerto/prevención & control , Inmunización , Terapia de Inmunosupresión , Interleucina-10/inmunología , Isoantígenos/inmunología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/efectos de la radiación , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de la radiación , Linfocitos T Reguladores/trasplante , Rayos Ultravioleta/efectos adversos
15.
World J Transplant ; 5(1): 11-8, 2015 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-25815267

RESUMEN

After the first observation of the immunosuppressive effects of ultraviolet (UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells (Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40(th) anniversary of its discovery.

16.
Cancer Immun ; 3: 16, 2003 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-14629132

RESUMEN

In this study, we identified a c-erbB-2/HER2/neu (HER2)-derived Th epitope (HER2 (16-30) ) and examined the role of Th epitopes in HER2-specific CD8+ T cell induction and in vivo tumor eradication, with a particular emphasis on the role of tumor cell-derived Th epitopes. Immunization of BALB/c mice using a mixture of Th epitope HER2 (16-30) and CTL epitope HER2 (63-71) administered subcutaneously with murine GM-CSF (mGM-CSF) induced a much higher level of HER2 (63-71) -specific CD8+ T cells compared with that obtained with the CTL epitope alone. HER2-unrelated OVA-derived Th epitope (OVA (323-339) ) exhibited a similar enhancing effect on HER2 (63-71) -specific CD8+ T cell induction. However, only mice immunized with HER2 (16-30) and HER2 (63-71), but not with a tumor-unrelated OVA (323-339) and HER2 (63-71), showed in vivo eradication of CMS5mHE tumor cells expressing HER2 but not OVA. This distinction was observed in preventative as well as therapeutic experimental settings. Conversely, both HER2 (16-30) and OVA (323-339) Th epitopes were equally effective in inducing the eradication of CMS5mHEOVA tumor cells which express HER2 as well as OVA. Our results clearly indicate that CTL and Th epitopes of target tumor cell origin should be used for effective induction of in vivo antitumor immunity.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Vacunas contra el Cáncer/administración & dosificación , Activación de Linfocitos/efectos de los fármacos , Neoplasias Experimentales/prevención & control , Receptor ErbB-2/administración & dosificación , Animales , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Trasplante de Neoplasias , Péptidos/administración & dosificación , Péptidos/inmunología , Receptor ErbB-2/inmunología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Am J Surg ; 184(5): 460-4, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12433614

RESUMEN

BACKGROUND: We investigated whether vascular endothelial growth factor (VEGF) plays an important role in maintaining constant tumor growth in wasted elderly patients, in whom oxygen and glucose supply are often unable to meet the demands of the body. METHODS: Tissue concentrations of VEGF in 70 gastric carcinomas and 70 normal mucosas were determined. The expression of VEGF was evaluated immunohistochemically. RESULTS: The net balance between the concentration of VEGF in the cancer and normal mucosa (VEGF Ca/N ratio: the cancer tissue VEGF concentration divided by normal mucosa VEGF concentration) increased with age and was associated with disease progression only in elderly patients. VEGF Ca/N ratio increased in response to systemic hypo-oxygenation and nutritional depletion only in elderly patients. CONCLUSIONS: The systemic-local regulating mechanism of VEGF production may play an important role in the constant growth of tumor cells, especially in elderly gastric cancer patients.


Asunto(s)
Factores de Crecimiento Endotelial/análisis , Péptidos y Proteínas de Señalización Intercelular/análisis , Linfocinas/análisis , Neoplasias Gástricas/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Factores de Crecimiento Endotelial/biosíntesis , Factores de Crecimiento Endotelial/farmacología , Femenino , Mucosa Gástrica/química , Humanos , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/farmacología , Linfocinas/biosíntesis , Linfocinas/farmacología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
18.
Parasitol Int ; 51(2): 177-86, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12113756

RESUMEN

Effects of Schistosoma mansoni infection on anti-tumor immunity were examined in CBF1 mice with ultraviolet-induced UVfemale1 fibrosarcoma cells. Although many laboratory established tumor cells had rejection mechanisms independent of CD4(+) T cells, we confirmed that CD4(+) cells had significant roles in rejection of UVfemale1 cells in the syngeneic CBF1 mice. When we prepared two CBF1 mouse groups, S. mansoni-infected and schistosome-free, the former group showed up-regulation of Th2-like response to UVfemale1 cells, whereas the latter group mice showed rather type 1-dominant patterns. Cytotoxic activity against UVfemale1 cells tested in vitro, which was attributed to CD8(+) cells, was significantly weaker in S. mansoni-infected mice compared with infection-free mice. In tumor challenge experiments in vivo, we observed that rapid and complete rejection of UVfemale1 cells required the presence of CD8(+) T cells. Under only CD4-depleted situation, survival of tumor cells in schistosome-free mice was prolonged up to 1 month or more. Under the presence of both CD4(+) and CD8(+) cells, S. mansoni infected mice rejected the challenged UVfemale1 cells as was seen in normal mice. However, when CD8(+) cells were depleted from S. mansoni-infected mice, inoculated UVfemale1 cells grew more rapidly than in infection-free mice. Our results suggest that functionally polarized cytokine patterns in schistosome-infected hosts promote rapid tumor growth.


Asunto(s)
Fibrosarcoma/inmunología , Fibrosarcoma/fisiopatología , Rechazo de Injerto/inmunología , Neoplasias de Tejido Fibroso/inmunología , Neoplasias de Tejido Fibroso/fisiopatología , Esquistosomiasis mansoni/inmunología , Células TH1/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/biosíntesis , Femenino , Fibrosarcoma/etiología , Inmunización , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neoplasias de Tejido Fibroso/etiología , Schistosoma mansoni/inmunología , Trasplante Isogénico , Células Tumorales Cultivadas , Rayos Ultravioleta/efectos adversos
19.
Ann Transplant ; 19: 519-36, 2014 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-25322948

RESUMEN

BACKGROUND: The use of ultraviolet (UV)-B irradiation after alloantigen immunization is unknown because previous studies focused on UV-B irradiation before immunization. Here, we investigated immunosuppressive effects induced by UV-B irradiation after immunization, and examined the phenotype of induced regulatory T cells and the possible mechanism of induction. MATERIAL AND METHODS: B6 mice (H-2(b)) were intravenously immunized by splenocytes from CBF1 mice (H-2(b/d)). One week after alloantigen immunization, B6 mice received high-dose UV-B irradiation (40 kJ/m(2)). Four weeks after UV-B irradiation, proliferation assays (n=4, in each), transplantations with skin or cardiac allografts (n=5, in each), cytokines in mixed lymphocyte culture (n=6, in each), and adoptive transfer of CD4(+) T cells to naïve B6 mice (n=5, in each) were performed. Mice were divided into 4 groups: untreated control, immunized control, UV-irradiated control, and an immunized and UV-irradiated group. B6C3F1 mice (H-2(b/k)) were used as irrelevant alloantigen with immunization controls. Anti-IL-10 monoclonal antibody was used to block IL-10 before and after UV-B irradiation. RESULTS: Immune responses against the immunizing antigen were markedly suppressed in immunized and UV-irradiated mice in an alloantigen-specific manner. Surprisingly, CD4(+) T cells from immunized and UV-irradiated mice produced significantly larger amounts of IL-10, in an alloantigen-specific manner. Moreover, alloantigen-specific immunosuppression via CD4(+) regulatory T cells was transferable to naïve B6 mice. IL-10 blocking clearly abrogated alloantigen-specific immunosuppression, indicating that UV-B irradiation evoked T regulatory type 1 cells. CONCLUSIONS: This study demonstrates for the first time that immunization and UV irradiation induces alloantigen-specific CD4(+) T regulatory type 1 cells, and that IL-10 plays an important role for this induction.


Asunto(s)
Trasplante de Corazón , Isoantígenos/administración & dosificación , Trasplante de Piel , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de la radiación , Traslado Adoptivo , Animales , Anticuerpos Bloqueadores/administración & dosificación , Citocinas/metabolismo , Células Dendríticas/inmunología , Relación Dosis-Respuesta en la Radiación , Femenino , Supervivencia de Injerto/inmunología , Inmunización , Terapia de Inmunosupresión/métodos , Interleucina-10/antagonistas & inhibidores , Interleucina-10/metabolismo , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Modelos Inmunológicos , Proyectos Piloto , Linfocitos T Reguladores/clasificación , Trasplante Homólogo , Rayos Ultravioleta
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