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1.
Sci Transl Med ; 11(499)2019 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-31270273

RESUMEN

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.


Asunto(s)
Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Proteínas del Ojo/metabolismo , Retina/metabolismo , Retina/patología , Proteínas de Unión al Retinol/metabolismo , 3-O-Metilglucosa/metabolismo , Ácidos/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Desoxiglucosa/metabolismo , Diabetes Mellitus/fisiopatología , Retinopatía Diabética/fisiopatología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Ependimogliales/efectos de los fármacos , Células Ependimogliales/metabolismo , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/sangre , Proteínas del Ojo/química , Glucólisis/efectos de los fármacos , Humanos , Inyecciones Intravítreas , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/patología , Sustancias Protectoras/farmacología , Dominios Proteicos , Ratas Endogámicas Lew , Proteínas Recombinantes/farmacología , Reproducibilidad de los Resultados , Retina/fisiopatología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/química , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Cuerpo Vítreo/efectos de los fármacos , Cuerpo Vítreo/metabolismo
2.
Mol Pharm ; 15(7): 2539-2547, 2018 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-29912566

RESUMEN

In the present study, tissue distribution and the therapeutic effect of topically applied cyclosporine A (CsA)-loaded methoxy-poly(ethylene-glycol)-hexyl substituted poly(lactic acid) (mPEGhexPLA) nanocarriers (ApidSOL) on experimental autoimmune uveitis (EAU) were investigated. The CsA-loaded mPEGhexPLA nanocarrier was tolerated well locally and showed no signs of immediate toxicity after repeated topical application in mice with EAU. Upon unilateral CsA treatment, CsA accumulated predominantly in the corneal and sclera-choroidal tissue of the treated eye and in lymph nodes (LN). This regimen reduced EAU severity in treated eyes compared to PBS-treated controls. This improvement was accompanied by reduced T-cell count, T-cell proliferation, and IL-2 secretion of cells from ipsilateral LN. In conclusion, topical treatment with CsA-loaded mPEGhexPLA nanocarriers significantly improves the outcome of EAU.


Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Ciclosporina/administración & dosificación , Portadores de Fármacos/química , Inmunosupresores/administración & dosificación , Uveítis/tratamiento farmacológico , Administración Oftálmica , Animales , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Humanos , Ratones , Nanopartículas/química , Poliésteres/química , Polietilenglicoles/química , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Resultado del Tratamiento , Uveítis/inmunología
3.
Clin Exp Immunol ; 183(2): 280-93, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26400205

RESUMEN

The aim of this study was to examine whether macrophage migration inhibitory factor (MIF) could exaggerate inflammatory response in a mouse model of experimental autoimmune uveitis (EAU) and to explore the underlying mechanism. Mutant serotype 8 adeno-associated virus (AAV8) (Y733F)-chicken ß-actin (CBA)-MIF or AAV8 (Y733F)-CBA-enhanced green fluorescent protein (eGFP) vector was delivered subretinally into B10.RIII mice, respectively. Three weeks after vector delivery, EAU was induced with a subcutaneous injection of a mixture of interphotoreceptor retinoid binding protein (IRBP) peptide with CFA. The levels of proinflammatory cytokines were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Retinal function was evaluated with electroretinography (ERG). We found that the expression of MIF and its two receptors CD74 and CD44 was increased in the EAU mouse retina. Compared to AAV8.CBA.eGFP-injected and untreated EAU mice, the level of proinflammatory cytokines, the expression of Notch1, Notch4, delta-like ligand 4 (Dll4), Notch receptor intracellular domain (NICD) and hairy enhancer of split-1 (Hes-1) increased, but the ERG a- and b-wave amplitudes decreased in AAV8.CBA.MIF-injected EAU mice. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) reduced the expression of NICD, Hes-1 and proinflammatory cytokines. Further, a MIF antagonist ISO-1 attenuated intraocular inflammation, and inhibited the differentiation of T helper type 1 (Th1) and Th17 in EAU mice. We demonstrated that over-expression of MIF exaggerated ocular inflammation, which was associated with the activation of the Notch signalling. The expression of both MIF and its receptors are elevated in EAU mice. Over-expression of MIF exaggerates ocular inflammation, and this exaggerated inflammation is associated with the activation of the Notch signalling and Notch pathway. Our data suggest that the MIF-Notch axis may play an important role in the pathogenesis of EAU. Both the MIF signalling pathways may be promising targets for developing novel therapeutic interventions for uveitis.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Oxidorreductasas Intramoleculares/fisiología , Factores Inhibidores de la Migración de Macrófagos/fisiología , Receptores Notch/fisiología , Retina/inmunología , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/terapia , Citocinas/genética , Dependovirus/genética , Modelos Animales de Enfermedad , Electrorretinografía , Ensayo de Inmunoadsorción Enzimática , Proteínas del Ojo/administración & dosificación , Femenino , Vectores Genéticos , Oxidorreductasas Intramoleculares/genética , Factores Inhibidores de la Migración de Macrófagos/genética , Masculino , Ratones , Ratones Endogámicos , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Notch/inmunología , Retina/fisiopatología , Retina/ultraestructura , Proteínas de Unión al Retinol/administración & dosificación , Transducción de Señal , Células TH1/inmunología , Células Th17/inmunología , Uveítis/metabolismo , Uveítis/fisiopatología , Uveítis/terapia
4.
EMBO Mol Med ; 7(6): 819-30, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25864124

RESUMEN

Activated hepatic stellate cells (HSCs) play a key role in liver fibrosis, and inactivating HSCs has been considered a promising therapeutic approach. We previously showed that albumin and its derivative designed for stellate cell-targeting, retinol-binding protein-albumin domain III fusion protein (referred to as R-III), inactivate cultured HSCs. Here, we investigated the mechanism of action of albumin/R-III in HSCs and examined the anti-fibrotic potential of R-III in vivo. R-III treatment and albumin expression downregulated retinoic acid (RA) signaling which was involved in HSC activation. RA receptor agonist and retinaldehyde dehydrogenase overexpression abolished the anti-fibrotic effect of R-III and albumin, respectively. R-III uptake into cultured HSCs was significantly decreased by siRNA-STRA6, and injected R-III was localized predominantly in HSCs in liver. Importantly, R-III administration reduced CCl4- and bile duct ligation-induced liver fibrosis. R-III also exhibited a preventive effect against CCl4-inducd liver fibrosis. These findings suggest that the anti-fibrotic effect of albumin/R-III is, at least in part, mediated by downregulation of RA signaling and that R-III is a good candidate as a novel anti-fibrotic drug.


Asunto(s)
Albúminas/metabolismo , Células Estrelladas Hepáticas/efectos de los fármacos , Cirrosis Hepática/prevención & control , Proteínas de Unión al Retinol/metabolismo , Albúminas/administración & dosificación , Albúminas/genética , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Estrelladas Hepáticas/fisiología , Histocitoquímica , Humanos , Inmunohistoquímica , Hígado/patología , Cirrosis Hepática/patología , Masculino , Ratones Endogámicos BALB C , Microscopía , Ratas Sprague-Dawley , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/genética , Transducción de Señal/efectos de los fármacos , Tretinoina/metabolismo
5.
J Neuroimmunol ; 263(1-2): 98-107, 2013 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-24029580

RESUMEN

We report here identification of novel mimicry epitopes for interphotoreceptor retinoid-binding protein (IRBP) 201-216, a candidate ocular antigen that causes experimental autoimmune uveoretinitis (EAU) in A/J mice. One mimicry epitope from Ehrlichia canis (EHC), designated EHC 44-59, induced cross-reactive T cells for IRBP 201-216 capable of producing T helper (Th)1 and Th17 cytokines, but failed to induce EAU in A/J mice. In addition, animals first primed with suboptimal doses of IRBP 201-216 and subsequently immunized with EHC 44-59 did not develop EAU; rather, the mimicry epitope prevented the disease induced by IRBP 201-216. However, alteration in the composition of EHC 44-59 by substituting alanine with valine at position 49, similar to the composition of IRBP 201-216, enabled the mimicry epitope to acquire uveitogenicity. The data provide new insights as to how microbes containing mimicry sequences for retinal antigens can prevent ocular inflammation by acting as naturally occurring altered peptide ligands.


Asunto(s)
Enfermedades Autoinmunes del Sistema Nervioso/prevención & control , Ehrlichia canis/inmunología , Ehrlichiosis/prevención & control , Imitación Molecular/inmunología , Retinitis/prevención & control , Uveítis/prevención & control , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/microbiología , Bovinos , Ehrlichia canis/genética , Ehrlichiosis/inmunología , Ehrlichiosis/microbiología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Femenino , Ligandos , Ratones , Ratones Endogámicos A , Datos de Secuencia Molecular , Retinitis/inmunología , Retinitis/microbiología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/genética , Proteínas de Unión al Retinol/metabolismo , Uveítis/inmunología , Uveítis/microbiología
6.
Mol Vis ; 18: 1858-64, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22815639

RESUMEN

PURPOSE: SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. METHODS: SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immunosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. RESULTS: SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-γ and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-γ transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT/Def6 KO mice resembled their wild type (WT) controls, however, in the levels of their serum antibody against IRBP, the antigen presenting capacity of their dendritic cells, the proportion of cells expressing Foxp3 and the immunosuppressive activity of their T-regulatory cells. CONCLUSIONS: SLAT/Def6 KO mice exhibit reduced capacity to develop ocular inflammation and cellular activity when immunized with IRBP. Our study provides new data showing that SLAT/Def6 plays a major role in the T cell-mediated autoimmune processes that bring about the inflammatory eye disease, EAU.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Proteínas de Unión al ADN/inmunología , Proteínas del Ojo/inmunología , Inflamación/inmunología , Proteínas Nucleares/inmunología , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Animales , Anticuerpos/sangre , Anticuerpos/inmunología , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/genética , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Proteínas del Ojo/administración & dosificación , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/inmunología , Factores de Intercambio de Guanina Nucleótido , Inflamación/inducido químicamente , Inflamación/genética , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ratones , Ratones Noqueados , Proteínas Nucleares/deficiencia , Proteínas Nucleares/genética , Toxina del Pertussis/administración & dosificación , Proteínas de Unión al Retinol/administración & dosificación , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/patología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/patología , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/patología , Uveítis/inducido químicamente , Uveítis/genética
7.
Immunol Lett ; 141(1): 83-93, 2011 Dec 30.
Artículo en Inglés | MEDLINE | ID: mdl-21896286

RESUMEN

This study evaluates the effects of pristane and phytol, two mineral oils with pro-oxidative effects, on the course of experimental autoimmune uveitis. C57BL6 mice were immunized with IRBP1-20 peptide emulsified in CFA and treated five days prior to immunization with phytol or with pristane or with PBS as control. Administration of pristane reduces the incidence and severity of IRBP-induced uveitis as demonstrated by the decrease in vasculitis and inflammatory foci in fundus and by a reduction in histological damages and leukocyte infiltration compared to untreated or phytol-treated mice. The protective effect observed is associated with a decreased activation of peripheral CD4+ and CD8+ T lymphocytes and a decrease in the intensity of the Th1 and Th17 autoimmune response to IRBP in pristane-treated mice compared to control mice, as evidenced by the decreased production of IFNγ and IL17 by IRBP-specific lymphocytes from lymph nodes draining the site of immunization and by the increased production of anti-IRBP IgG1 over IgG2a. In addition, HUVEC and ARPE-19 cells incubated with the sera of mice treated with pristane presented a reduced production of H(2)O(2). The benefit of lowering the systemic oxidative stress by pristane in the course of EAU was confirmed by injecting the antioxidant NAC in IRBP-immunized mice. As pristane, NAC decreased clinical and histological inflammation of the retina and preserved the integrity of the hemato-retinal barrier. Finally, the protective effect of pristane on the development of EAU suggests that some mineral oils may represent a new therapeutic strategy in human uveitis.


Asunto(s)
Proteínas del Ojo , Ojo/patología , Proteínas de Unión al Retinol , Terpenos/administración & dosificación , Uveítis , Acetilcisteína/administración & dosificación , Animales , Autoinmunidad/inmunología , Línea Celular , Modelos Animales de Enfermedad , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Células Endoteliales de la Vena Umbilical Humana , Humanos , Peróxido de Hidrógeno/análisis , Inmunización , Inmunoglobulina G/sangre , Interleucina-17/análisis , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Fitol/administración & dosificación , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Uveítis/patología , Uveítis/prevención & control
8.
Mol Vis ; 17: 1814-21, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21850155

RESUMEN

PURPOSE: Posttranslational modification of proteins plays an important role in cellular functions and is a key event in signal transduction pathways leading to oxidative stress and DNA damage. In this study, we used matrix-assisted laser desorption/ionization- time of flight (MALDI-TOF) to investigate the posttranslational modifications of the differentially expressed proteins in the retinal mitochondria during early experimental autoimmune uveitis (EAU). METHODS: EAU was induced in 18 B10RIII mice with 25 µg of inter-photoreceptor retinoid-binding protein (IRBP) emulsified with complete Freund's adjuvant (CFA); 18 mice treated with CFA without IRBP served as controls. Retinas were removed from the experimental and control groups on day 7 post immunization; mitochondrial fractions were extracted and subjected to 2 dimentional-difference in gel electrophoresis (2D-DIGE); and the protein spots indicating differential expression were subjected to MALDI-TOF for protein identification and indication of any posttranslational modifications. RESULTS: Of the 13 proteins found to be differentially expressed by 2D-DIGE (including upregulated aconitase, mitochondrial heat shock protein (mtHsp) 70, lamin-1, syntaxin-binding protein, αA crystallin, ßB2 crystallin, along with downregulated guanine nucleotide-binding protein and ATP synthase) nine were found to undergo posttranslational modification. Oxidation was a common modification found to occur on aconitase, mtHsp 70, ATP synthase, lamin-1, ßB2-crystallin, guanine nucleotide-binding protein, and manganese superoxide dismutase (MnSOD). In addition, aconitase hydratase, mtHsp 70, guanine nucleotide-binding protein, ATP synthase, syntaxin-binding protein, ßB2-crystallin, and lamin-1 were also modified by carbamidomethylation. αA-crystallin had a pyro-glu modification. CONCLUSIONS: Several proteins present in the retinal mitochondria are posttranslationally modified during early EAU, indicating the presence of oxidative stress and mitochondrial DNA damage. The most common modifications are oxidation and carbamidomethylation. A better understanding of the proteins susceptible to posttranslational modifications in the mitochondria at the early stage of the disease may serve to advance therapeutic interventions to attenuate disease progression.


Asunto(s)
Enfermedades Autoinmunes/genética , Proteínas del Ojo/inmunología , Mitocondrias/genética , Proteínas Mitocondriales/genética , Péptidos/inmunología , Procesamiento Proteico-Postraduccional , Retina/metabolismo , Proteínas de Unión al Retinol/inmunología , Uveítis/genética , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Modelos Animales de Enfermedad , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/efectos adversos , Adyuvante de Freund/administración & dosificación , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos , Mitocondrias/química , Mitocondrias/inmunología , Mitocondrias/metabolismo , Proteínas Mitocondriales/inmunología , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Estrés Oxidativo , Péptidos/administración & dosificación , Péptidos/efectos adversos , Procesamiento Proteico-Postraduccional/genética , Procesamiento Proteico-Postraduccional/inmunología , Retina/inmunología , Retina/patología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/efectos adversos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Electroforesis Bidimensional Diferencial en Gel , Uveítis/inducido químicamente , Uveítis/inmunología , Uveítis/metabolismo , Uveítis/patología
9.
J Immunol ; 183(1): 560-7, 2009 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-19542467

RESUMEN

We show that in vitro activation of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells from C57BL/6 mice immunized with an uveitogenic IRBP peptide (IRBP(1-20)) under TH17-polarizing conditions is associated with increased expansion of T cells expressing the gammadelta TCR. We also show that highly purified alphabeta or gammadelta T cells from C57BL/6 mice immunized with IRBP(1-20) produced only small amounts of IL-17 after exposure to the immunizing Ag in vitro, whereas a mixture of the same T cells produced greatly increased amounts of IL-17. IRBP-induced T cells from IRBP-immunized TCR-delta(-/-) mice on the C57BL/6 genetic background produced significantly lower amounts of IL-17 than did wild-type C57BL/6 mice and had significantly decreased experimental autoimmune uveitis-inducing ability. However, reconstitution of the TCR-delta(-/-) mice before immunization with a small number of gammadelta T cells from IRBP-immunized C57BL/6 mice restored the disease-inducing capability of their IRBP-specific T cells and greatly enhanced the generation of IL-17(+) T cells in the recipient mice. Our study suggests that gammadelta T cells are important in the generation and activation of IL-17-producing autoreactive T cells and play a major role in the pathogenesis of experimental autoimmune uveitis.


Asunto(s)
Diferenciación Celular/inmunología , Interleucina-17/biosíntesis , Receptores de Antígenos de Linfocitos T gamma-delta/biosíntesis , Linfocitos T Colaboradores-Inductores/inmunología , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Comunicación Celular/genética , Comunicación Celular/inmunología , Diferenciación Celular/genética , Polaridad Celular/genética , Polaridad Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Epítopos de Linfocito T/administración & dosificación , Epítopos de Linfocito T/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Interleucina-17/fisiología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/deficiencia , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología , Uveítis/genética , Uveítis/patología
10.
J Immunol ; 181(7): 4791-7, 2008 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-18802082

RESUMEN

Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with alpha-C-GalCer, which induces a strong IFN-gamma but only a weak IL-4 production by iNKT cells, in contrast to the ligands alpha-GalCer (both IFN-gamma and IL-4) and OCH (primarily IL-4). The protective effect of alpha-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-gamma and IL-17 production and was negated by systemic neutralization of IFN-gamma. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-gamma and a consequent dampening of the Th1 as well as the Th17 effector responses.


Asunto(s)
Enfermedades Autoinmunes/terapia , Interferón gamma/biosíntesis , Interleucina-17/fisiología , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Células TH1/inmunología , Uveítis/terapia , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/prevención & control , Bovinos , Susceptibilidad a Enfermedades/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Inmunidad Innata , Interferón gamma/metabolismo , Interferón gamma/fisiología , Interleucina-17/antagonistas & inhibidores , Interleucina-4/metabolismo , Ligandos , Ratones , Ratones Endogámicos AKR , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Especificidad de la Especie , Células TH1/metabolismo , Uveítis/inmunología , Uveítis/prevención & control
11.
Int Immunol ; 20(2): 209-14, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18156624

RESUMEN

IL-17-producing CD4(+) T cells, so called T(h)17 cells, constitute a newly identified inflammatogenic cell population, which is critically involved in some inflammatory diseases. To explore the role of T(h)17 cells in murine experimental autoimmune uveoretinitis (EAU), a model of human autoimmune uveitis where T(h)1 responses predominantly participate in the pathogenesis, IL-17(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 for disease induction. Funduscopic examination revealed that EAU was induced in IL-17(-/-) mice just like in wild-type (WT) mice at early phases of the disease. However, at later/maintenance phases, the severity was significantly reduced in IL-17(-/-) mice. Expression of IFN-gamma and MCP-1 was comparable between WT and IL-17(-/-) mice during the time course. In vivo blockade of IFN-gamma and IL-4 resulted in exacerbation of EAU at later phases with augmented IL-17 production. Taken together, our data demonstrated that IL-17/T(h)17 participates in the late phases of EAU and also that T(h)1 and T(h)17 responses are differentially required for EAU.


Asunto(s)
Enfermedades Autoinmunes , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Retinitis , Uveítis , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/fisiopatología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/química , Proteínas del Ojo/toxicidad , Humanos , Inflamación/inmunología , Inflamación/fisiopatología , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-17/genética , Interleucina-17/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Retinitis/inducido químicamente , Retinitis/inmunología , Retinitis/fisiopatología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/química , Proteínas de Unión al Retinol/toxicidad , Células TH1 , Uveítis/inducido químicamente , Uveítis/inmunología , Uveítis/fisiopatología
12.
J Immunol ; 179(8): 5146-58, 2007 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-17911600

RESUMEN

The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 microg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8(+) cells, IL-10, or TGF-beta. In contrast, depletion of CD25(+) cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4(+)CD25(high) T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3(+)CD4(+)CD25(+) regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.


Asunto(s)
Enfermedades Autoinmunes/prevención & control , Diferenciación Celular/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Linfocitos T Reguladores/inmunología , Uveítis/prevención & control , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/genética , Diferenciación Celular/genética , Células Cultivadas , Proteínas del Ojo/genética , Humanos , Inyecciones a Chorro , Hígado/inmunología , Hígado/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia Molecular , Proteínas de Unión al Retinol/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Linfocitos T Reguladores/citología , Uveítis/genética , Uveítis/inmunología , Vacunas de ADN/genética
13.
J Immunol ; 175(3): 1851-7, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16034128

RESUMEN

We previously demonstrated that cultures of rat uveitogenic T cells rapidly become dominated by CD4+ cells, but activation of CD8+ autoreactive T cells also occurred during the in vitro culture of in vivo-primed T cells. In the present study, we show that the commonly used uveitogenic peptide, interphotoreceptor retinoid-binding protein (IRBP) 1-20, generated both CD4+ and CD8+ autoreactive T cells in the C57BL/6 (B6) mouse and that this 20-mer contains at least two distinct antigenic epitopes. To determine whether the CD8 response was Ag-specific and whether CD4+ and CD8+ IRBP1-20-specific T cells recognize distinct antigenic epitopes, we prepared highly purified CD4+ and CD8+ T cells from IRBP1-20-primed mice and tested their proliferative response to a large panel of truncated peptides derived from IRBP1-20. The results showed that both CD4+ and CD8+ T cells recognized the same spectrum of peptides. In addition, peptides P10-18 were found to bind effectively to CD8+ IRBP1-20-specific T cells when complexed with recombinant H-2K(b) and also stimulate the proliferation and cytokine production of CD4+ IRBP1-20-specific T cells. Our results document for the first time that CD8+ and CD4+ autoreactive T cells display characteristic epitope recognition and they both recognize the same core epitope.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/metabolismo , Proteínas del Ojo/metabolismo , Proteínas de Unión al Retinol/metabolismo , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/trasplante , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Separación Celular , Epítopos de Linfocito T/administración & dosificación , Epítopos de Linfocito T/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Antígenos H-2/inmunología , Antígenos H-2/metabolismo , Antígeno de Histocompatibilidad H-2D , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Unión Proteica/inmunología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Uveítis/patología
14.
J Neuroimmunol ; 163(1-2): 102-9, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15885312

RESUMEN

Recurrent uveitis is a common cause of vision blindness. Using a rat model of chronic recurrent uveitis, we examined the relationship between clinical expression, pathological changes, and the heterogeneity of the disease. Chronic recurrent uveitis was induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in a total of more than 60 Lewis rats. In about 75% of cases recurrent uveitis was pathologically a chronic and progressive disease. The major pathological changes included the gradual loss of photoreceptor cells. However, disease progression did not always parallel the severity of ocular inflammation and clinical recurrent disease, with about a quarter showing no pathological damage in the eye.


Asunto(s)
Traslado Adoptivo , Epítopos de Linfocito T/inmunología , Células Fotorreceptoras de Vertebrados/inmunología , Células Fotorreceptoras de Vertebrados/patología , Proteínas de Unión al Retinol/inmunología , Linfocitos T/trasplante , Uveítis/inmunología , Uveítis/patología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Ratas , Ratas Endogámicas Lew , Recurrencia , Proteínas de Unión al Retinol/administración & dosificación , Linfocitos T/inmunología
15.
J Immunol ; 174(1): 143-54, 2005 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-15611236

RESUMEN

A single exposure to inhaled Ag 10 days before immunization leads to long term, Ag-specific tolerance. Respiratory tract myeloid APCs are implicated, but how regulation is invoked, and how tolerance is sustained are unclear. This study examines the in vivo function of the myeloid regulatory molecule CD200 in the process of tolerance induction. Despite earlier onset of experimental autoimmune uveitis in sham-tolerized, CD200-deficient mice, disease incidence and subsequent severity were actually reduced compared with those in wild-type mice. Protection was more effective and long term, lasting at least 28 days. Halting disease progression and tolerance in CD200(-/-) mice correlated with a marked increase in Th2-associated cytokine production by Ag-challenged splenocytes. Reduced overall disease and enhanced tolerance in the CD200-deficient mice in this model system were unexpected and may be related to altered populations of MHC class II(low) APC in the respiratory tract compared with wild-type mice together with associated activation of STAT6 in draining lymph nodes of tolerized mice. These data indicate that in the absence of default inhibitory CD200 receptor signaling, alternative, powerful regulatory mechanisms are invoked. This may represent either permissive dominant Th2 activation or an altered hierarchy of negative signaling by other myeloid cell-expressed regulatory molecules.


Asunto(s)
Variación Antigénica/inmunología , Tolerancia Inmunológica/inmunología , Glicoproteínas de Membrana/deficiencia , Células Th2/inmunología , Uveítis/inmunología , Administración por Inhalación , Animales , Células Presentadoras de Antígenos/inmunología , Citocinas/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Citometría de Flujo , Inmunohistoquímica , Inmunofenotipificación , Inmunoprecipitación , Pulmón/citología , Pulmón/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Glicoproteínas de Membrana/inmunología , Ratones , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Factor de Transcripción STAT6 , Bazo/citología , Bazo/inmunología , Transactivadores/inmunología
16.
Methods Mol Med ; 102: 395-419, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15286397

RESUMEN

The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions.


Asunto(s)
Enfermedades Autoinmunes/etiología , Uveítis/etiología , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Arrestina/administración & dosificación , Arrestina/genética , Arrestina/inmunología , Autoantígenos/administración & dosificación , Autoantígenos/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Bovinos , Modelos Animales de Enfermedad , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/genética , Proteínas del Ojo/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/inmunología , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/genética , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunología , Uveítis/patología , Vacunación
17.
J Immunol ; 171(10): 5624-30, 2003 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-14607971

RESUMEN

Autoimmune uveitis has been elicited in susceptible rodents by several ocular-specific Ags. In most of these animal models the induced uveitis is acute and monophasic. Because recurrent uveitis poses the highest risk for blinding ocular complications in human disease, a spontaneous relapsing animal model would be most helpful in understanding the disease pathogenesis. In our current study we have observed that the adoptive transfer of interphotoreceptor retinoid-binding protein residues 1177-1191-specific T cells to naive Lewis rats induced a chronic relapsing disease, in contrast to the monophasic disease induced by immunization with interphotoreceptor retinoid-binding protein residues 1177-1191 emulsified in CFA. The chronic relapsing uveitis induced by autoreactive T cell subsets is dependent on the number of autoreactive T cells generated as well as their activation status. Our study documented a spontaneous model of recurrent uveitis in the rat, which should assist us in the study of disease pathogenesis and the design of specific therapy.


Asunto(s)
Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos T/inmunología , Uveítis/inmunología , Traslado Adoptivo , Animales , Autoantígenos/administración & dosificación , Enfermedades Autoinmunes/patología , Línea Celular Transformada , Movimiento Celular/inmunología , Supervivencia Celular/inmunología , Enfermedad Crónica , Relación Dosis-Respuesta Inmunológica , Epítopos de Linfocito T/inmunología , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Inmunización , Activación de Linfocitos/inmunología , Ratas , Ratas Endogámicas Lew , Recurrencia , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/trasplante , Uveítis/patología
18.
J Immunol ; 171(9): 4780-5, 2003 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-14568955

RESUMEN

Aberrant activation of autoreactive T cells is one of the major causes of autoimmune disease. Autoantigens are sequestered and in many cases weak immunogens. For example, in experimental autoimmune uveitis, immunization of naive rats with autologous interphotoreceptor retinoid-binding protein (IRBP) fails to induce intraocular inflammation or a strong T cell response, whereas bovine IRBP is a strong inducer of experimental autoimmune uveitis. Such observations challenge the view that the autoantigen alone is responsible for the development of autoimmunity. Here, we demonstrate that autologous rat IRBP is converted to a strong immunogen in the presence of a small dose of CpG-containing oligodeoxynucleotides. Our results indicate that specific CpG-containing oligodeoxynucleotides may play an important role in the activation and expansion of autoreactive T cells in vivo, leading to autoimmune disease.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Autoantígenos/inmunología , ADN/farmacología , Proteínas del Ojo , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Proteínas de Unión al Retinol/inmunología , Proteínas de Unión al Retinol/metabolismo , Uveítis/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Traslado Adoptivo , Secuencia de Aminoácidos , Animales , Autoantígenos/administración & dosificación , Autoantígenos/metabolismo , Autoantígenos/fisiología , Enfermedades Autoinmunes/inmunología , Bovinos , Línea Celular , Islas de CpG/inmunología , ADN/administración & dosificación , Relación Dosis-Respuesta Inmunológica , Combinación de Medicamentos , Femenino , Activación de Linfocitos/efectos de los fármacos , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/fisiología , Ratas , Ratas Endogámicas Lew , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/fisiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante
19.
J Immunol ; 170(4): 1728-36, 2003 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-12574336

RESUMEN

Pertussis toxin (PTX) has been widely used as an adjuvant to induce Th1-mediated organ-specific autoimmune diseases in animal models. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that dendritic cells (DC) stimulated with PTX (PTX-DC) were able to substitute for PTX to promote experimental autoimmune uveitis (EAU). EAU induced by PTX-DC revealed a typical Th1 response, characterized by high uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP)-specific IFN-gamma and IL-12 production in the draining lymph nodes, as well as increased levels of anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum of IRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells to produce the Th1 cytokine, IFN-gamma. After being stimulated with PTX, DC exhibited up-regulation of MHC class II, CD80, CD86, CD40, and DEC205. PTX-DC had also increased allostimulatory capacity and IL-12 and TNF-alpha production. Serum IL-12 was increased in naive mice that received PTX-DC i.p. In addition, PTX activated extracellular signal-regulated kinase in DC. Following the inhibition of extracellular signal-regulated kinase signaling, the maturation of PTX-DC was reduced. Subsequently, the ability of PTX-DC to promote IFN-gamma production by T cells in vitro and to induce EAU in vivo was blocked. The results suggest that PTX might exert an adjuvant effect on DC to promote their maturation and the production of proinflammatory cytokines, thereby eliciting a Th1 response.


Asunto(s)
Adyuvantes Inmunológicos/farmacología , Células Dendríticas/inmunología , Toxina del Pertussis/farmacología , Células TH1/inmunología , Células TH1/metabolismo , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/fisiología , Animales , Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/citología , Células Dendríticas/enzimología , Células Dendríticas/trasplante , Proteínas del Ojo/administración & dosificación , Proteínas del Ojo/inmunología , Femenino , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Interferón gamma/biosíntesis , Interleucina-12/sangre , Interleucina-12/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Prueba de Cultivo Mixto de Linfocitos , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Endogámicos A , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Toxina del Pertussis/administración & dosificación , Toxina del Pertussis/fisiología , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Células TH1/enzimología , Uveítis/enzimología , Uveítis/etiología , Uveítis/inmunología , Uveítis/patología
20.
J Leukoc Biol ; 73(1): 57-64, 2003 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-12525562

RESUMEN

Methimazole (methyl-mercapto-imidazole, MMI), a compound used clinically in therapy of Graves' thyroiditis, was found to inhibit development of several autoimmune diseases in animal models. It was suggested on the basis of in vitro data that inhibition is through down-regulation of interferon-gamma (IFN-gamma)-induced expression of major histocompatibility complex class I and class II molecules. Here, we investigate the effect of MMI on experimental autoimmune uveoretinitis (EAU) and study its mechanism(s). Treatment of EAU with MMI administered in drinking water inhibited induction of the disease and associated antigen (Ag)-specific proliferation and cytokine production by draining lymph node cells (LNCs). The treatment was protective only if administered during the first but not during the second week after immunization, suggesting an effect on the induction phase of EAU. It is interesting that MMI inhibited disease in IFN-gamma knockout mice, indicating that the in vivo protective effect is IFN-gamma-independent. Flow cytometric analysis of draining LNCs extracted 5 days after immunization showed that MMI partly to completely reversed the increase in Mac-1(+)/class I(+)/class II(+) cells induced by immunization and reduced the proportion of B7-1 and CD40-positive cells, suggesting a deficit in the Ag-presenting cell (APC) population. APC from untreated mice largely restored antigen-specific proliferation of MMI-treated LNCs. We suggest that MMI inhibits EAU at least in part by preventing the recruitment and/or maturation of APC, resulting in reduced generation of Ag-specific T cells.


Asunto(s)
Presentación de Antígeno/efectos de los fármacos , Antitiroideos/farmacología , Enfermedades Autoinmunes/prevención & control , Proteínas del Ojo , Metimazol/farmacología , Uveítis/inmunología , Uveítis/prevención & control , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Antitiroideos/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Citocinas/análisis , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Interferón gamma/antagonistas & inhibidores , Interferón gamma/genética , Interferón gamma/farmacología , Ganglios Linfáticos/citología , Antígeno de Macrófago-1/análisis , Antígeno de Macrófago-1/efectos de los fármacos , Metimazol/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Retinitis/tratamiento farmacológico , Retinitis/inmunología , Retinitis/prevención & control , Proteínas de Unión al Retinol/administración & dosificación , Proteínas de Unión al Retinol/inmunología , Uveítis/tratamiento farmacológico
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