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1.
Mol Vis ; 26: 641-651, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33088168

RESUMEN

Purpose: Tofacitinib is a pan-Janus kinase (JAK) inhibitor that suppresses cytokine signaling and in turn, the cells that participate in inflammatory immunopathogenic processes. We examined the capacity of tofacitinib to inhibit the induction of experimental autoimmune uveitis (EAU) and related immune responses. Methods: EAU was induced in B10.A mice with immunization with bovine interphotoreceptor retinoid-binding protein (IRBP), emulsified in complete Freund's adjuvant (CFA), and a simultaneous injection of pertussis toxin. Tofacitinib, 25 mg/kg, was administered daily, and the vehicle was used for control. EAU development was assessed by histological analysis of the mouse eyes, and related immune responses were assessed by (i) the levels of interferon (IFN)-γ and interleukin (IL)-17, secreted by spleen cells cultured with IRBP; (ii) flow cytometric analysis of intracellular expression by spleen, or eye-infiltrating CD4 or CD8 cells of IFN-γ, IL-17, and their transcription factors, T-bet and RORγt. In addition, the inflammation-related cell markers CD44 and CD62L and Ki67, a proliferation marker, were tested. The proportions of T-regulatory cells expressing FoxP3 were determined by flow cytometric intracellular staining, while levels of antibody to IRBP were measured with enzyme-linked immunosorbent assay (ELISA). Results: Treatment with tofacitinib significantly suppressed the development of EAU and reduced the levels of secreted IFN-γ, but not of IL-17. Further, treatment with tofacitinib reduced in the spleen and eye-infiltrating cells the intracellular expression of IFN-γ and its transcription factor T-bet. In contrast, treatment with tofacitinib had essentially no effect on the intracellular expression of IL-17 and its transcription factor, RORγt. The selective effect of tofacitinib treatment was particularly evident in the CD8 population. Treatment with tofacitinib also increased the population of CD44, but reduced the populations of cells producing CD62L and Ki67. Treatment with tofacitinib had no effect on the proportion of FoxP3 producing regulatory cells and on the antibody production to IRBP. Conclusions: Treatment with tofacitinib inhibited the development of EAU, reduced the production of IFN-γ, but had essentially no effect on the production of IL-17.


Asunto(s)
Ojo/metabolismo , Piperidinas/farmacología , Pirimidinas/farmacología , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Uveítis/tratamiento farmacológico , Uveítis/inmunología , Animales , Antígenos CD4/sangre , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/sangre , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Ojo/efectos de los fármacos , Ojo/patología , Proteínas del Ojo/farmacología , Factores de Transcripción Forkhead/sangre , Receptores de Hialuranos/sangre , Terapia de Inmunosupresión , Interferón gamma/sangre , Interleucina-17/sangre , Antígeno Ki-67/sangre , Selectina L/sangre , Ratones , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Proteínas de Unión al Retinol/farmacología , Células TH1/inmunología , Células Th17/inmunología
2.
Eur J Immunol ; 48(11): 1810-1816, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30218573

RESUMEN

Experimental autoimmune uveitis (EAU), an animal model for severe intraocular inflammatory eye diseases, is mediated by both Th1 and Th17 cells. Here, we examined the capacity of TMP778, a selective inhibitor of RORγt, to inhibit the development of EAU, as well as the related immune responses. EAU was induced in B10.A mice by immunization with interphotoreceptor retinoid-binding protein (IRBP). Treatment with TMP778 significantly inhibited the development of EAU, determined by histological examination. In addition, the treatment suppressed the cellular immune response to IRBP, determined by reduced production of IL-17 and IFN-γ, as well as lower percentages of lymphocytes expressing these cytokines, as compared to vehicle-treated controls. The inhibition of IFN-γ expression by TMP778 is unexpected in view of this compound being a selective inhibitor of RORγt. The observation was further confirmed by the finding of reduced expression of the T-bet (Tbx21) gene, the transcription factor for IFN-γ, by cells of TMP778-treated mice. Thus, these data demonstrate the capacity of TMP778 to inhibit pathogenic autoimmunity in the eye and shed new light on its mode of action in vivo.


Asunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Uveítis/tratamiento farmacológico , Animales , Enfermedades Autoinmunes/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas del Ojo/metabolismo , Femenino , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones , Proteínas de Unión al Retinol/metabolismo , Proteínas de Dominio T Box/metabolismo , Células TH1/metabolismo , Células Th17/metabolismo , Uveítis/metabolismo
3.
J Immunol ; 198(2): 681-690, 2017 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-27986906

RESUMEN

Th cells sensitized against autoantigens acquire pathogenicity following two sequential events, namely activation by their target Ag and a process named "licensing." In this study, we analyzed these processes in a transgenic mouse system in which TCR-transgenic Th cells specific to hen egg lysozyme (HEL) are adoptively transferred to recipients and induce inflammation in eyes expressing HEL. Our data show that the notion that the lung is the organ where "licensing" for pathogenicity takes place is based on biased data collected with cells injected i.v., a route in which most transferred cells enter via the lung. Thus, we found that when donor cells were activated in vitro and injected intraperitoneally, or were activated in vivo, they migrated simultaneously to the lung, spleen, and other tested organs. In all, tested organs donor cells undergo "licensing" for pathogenicity, consisting of vigorous increase in number and changes in expression levels of inflammation-related genes, monitored by both flow cytometry and microarray analysis. After reaching peak numbers, around day 3, the "licensed" donor cells migrate to the circulation and initiate inflammation in the HEL-expressing recipient eyes. Importantly, the kinetics of increase in number and of changes in gene expression by the donor cells were similar in lung, spleen, and other tested organs of the recipient mice. Furthermore, the total numbers of donor cells in the spleen at their peaks were 10- to 100-fold larger in the spleen than in the lung, contradicting the notion that the lung is the organ where "licensing" takes place.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Traslado Adoptivo , Animales , Autoantígenos/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Pulmón/inmunología , Ratones , Ratones Transgénicos , Muramidasa/inmunología , Bazo/inmunología
4.
Exp Eye Res ; 166: 116-119, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29074386

RESUMEN

In this study we compared polarized mouse T-helper (Th) lymphocytes of four populations, sensitized against an ocular antigen, for their patterns of migration and induction of inflammatory processes in recipient mouse eyes expressing the target antigen. Th1, Th2, Th9 and Th17 cells transgenically expressing T-cell receptor (TCR) specific against hen egg lysozyme (HEL) were adoptively transferred to recipient mice expressing HEL in their eyes. Recipient eyes collected 4 or 7 days post injection were analyzed for histopathological changes. Th1 and Th17 cells induced moderate to severe intraocular inflammation in the recipient mouse eyes, but essentially did not migrate into the conjunctiva. In contrast, Th2 and Th9 cells invaded minimally the intraocular space of recipient eyes, but accumulated in the limbus and migrated into the conjunctiva of the recipient mice and initiated allergy-like inflammatory responses, as indicated by remarkable eosinophil involvement. These data thus shed new light on the differences between the migration patterns and ocular pathogenic processes mediated by Th1/Th17 and by Th2/Th9 populations.


Asunto(s)
Movimiento Celular , Conjuntiva/patología , Eosinofilia/patología , Limbo de la Córnea/parasitología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Modelos Animales de Enfermedad , Cristalino/metabolismo , Ratones , Muramidasa , Células TH1/inmunología , Células Th17/inmunología , Células Th2/inmunología
5.
Proc Natl Acad Sci U S A ; 112(13): 4080-5, 2015 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-25775512

RESUMEN

Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.


Asunto(s)
Ciclosporina/química , Glucocorticoides/química , Células Th17/citología , Animales , Autoinmunidad , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Calcineurina/química , Inhibidores de la Calcineurina/química , Núcleo Celular/metabolismo , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Inflamación , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones , Ratones Transgénicos , Fenotipo , Esteroides/química
6.
J Immunol ; 194(8): 3567-82, 2015 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-25786692

RESUMEN

The TNF family cytokine TL1A (Tnfsf15) costimulates T cells and type 2 innate lymphocytes (ILC2) through its receptor DR3 (Tnfrsf25). DR3-deficient mice have reduced T cell accumulation at the site of inflammation and reduced ILC2-dependent immune responses in a number of models of autoimmune and allergic diseases. In allergic lung disease models, immunopathology and local Th2 and ILC2 accumulation is reduced in DR3-deficient mice despite normal systemic priming of Th2 responses and generation of T cells secreting IL-13 and IL-4, prompting the question of whether TL1A promotes the development of other T cell subsets that secrete cytokines to drive allergic disease. In this study, we find that TL1A potently promotes generation of murine T cells producing IL-9 (Th9) by signaling through DR3 in a cell-intrinsic manner. TL1A enhances Th9 differentiation through an IL-2 and STAT5-dependent mechanism, unlike the TNF-family member OX40, which promotes Th9 through IL-4 and STAT6. Th9 differentiated in the presence of TL1A are more pathogenic, and endogenous TL1A signaling through DR3 on T cells is required for maximal pathology and IL-9 production in allergic lung inflammation. Taken together, these data identify TL1A-DR3 interactions as a novel pathway that promotes Th9 differentiation and pathogenicity. TL1A may be a potential therapeutic target in diseases dependent on IL-9.


Asunto(s)
Asma/inmunología , Diferenciación Celular/inmunología , Interleucina-9/inmunología , Miembro 25 de Receptores de Factores de Necrosis Tumoral/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/inmunología , Animales , Asma/genética , Asma/patología , Diferenciación Celular/genética , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Interleucina-13/genética , Interleucina-13/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-9/genética , Ratones , Ratones Noqueados , Miembro 25 de Receptores de Factores de Necrosis Tumoral/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/patología , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética
7.
J Immunol ; 191(1): 415-23, 2013 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-23720812

RESUMEN

The interaction between TLRs and their cognate ligands triggers both the innate and adaptive immune systems, and thus can play a pivotal role in the defense against pathogen invasion. This work investigates the differentiation of naive CD4 cells into Th1 or Th17 phenotypes in mice treated with different TLR ligands. We use a model system in which naive transgenic cells specific to hen egg lysozyme are adoptively transferred into recipients that express hen egg lysozyme in the lens of the eye. The transferred naive T cells induce ocular inflammation only in recipients treated with TLR ligands. Treatment with LPS preferentially stimulated IL-17 production, whereas CpG oligodeoxynucleotide and polyinosinic:polycytidylic acid primarily stimulated Th1 cells. Peptidoglycan stimulated the two Th subpopulations equally. The preferential induction of Th1 or Th17 by the four ligands was detected in the spleen (where a major portion of the adoptively transferred cells homed) and in the eyes, where activated Th cells initiate inflammation. Analysis of the cytokines present in recipient mice suggests that Th1 induction is elicited by IL-12 and/or IFN-α, whereas Th17 generation is preferentially mediated by IL-6. Importantly, we show in this article that treatment with LPS selectively promoted in the recipient mice the generation of IL-6-producing activated B cells. An inverse correlation was found between the level of regulatory T cells and severity of inflammation induced by the donor cells. Taken together, our data show that specific TLR ligands differentially activate the immune system as evidenced by the generation of distinct Th phenotypes from naive CD4 cells.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Células TH1/inmunología , Células Th17/inmunología , Receptores Toll-Like/metabolismo , Animales , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Pollos , Ligandos , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Muramidasa/genética , Peptidoglicano/metabolismo , Poli I-C/metabolismo , Células TH1/metabolismo , Células TH1/patología , Células Th17/metabolismo , Células Th17/patología , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 3/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 9/metabolismo , Receptores Toll-Like/fisiología
8.
Cell Immunol ; 290(2): 179-84, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25038545

RESUMEN

Regulatory T-cells (Tregs) are responsible for homeostasis of the immune system, as well as for inhibition of pathogenic autoimmune processes. Induced-(i)-Tregs, can be generated in vitro by activation of CD4 cells in the presence of TGF-ß. A commonly used activation mechanism is by antibodies against CD3 and CD28. The physiological-like activation of T-cells, however, is with the specific target antigen presented by antigen-presenting cells (APC). The two modes of activation have been considered to yield the same populations of iTregs. Here, we compared between iTreg populations generated by either one of the two methods and found differences between their capacities to inhibit T-lymphocyte proliferative response, their expression of cell surface antigens and particularly, in their transcript expression profiles of certain chemokines and chemokine receptors. Our data thus indicate that iTregs generated by activation with anti-CD3/CD28 antibodies cannot be considered identical to iTregs generated by antigen/APC.


Asunto(s)
Técnicas In Vitro/métodos , Activación de Linfocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos CD28/inmunología , Complejo CD3/inmunología , Citocinas/biosíntesis , Citometría de Flujo , Ratones , Ratones Transgénicos , Reacción en Cadena de la Polimerasa
9.
J Immunol ; 189(3): 1220-7, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-22745380

RESUMEN

Subpopulations of pathogenic or nonpathogenic Th17 cells were reported to develop when presensitized CD4 cells were activated with their target Ag during polarization by either IL-23 or IL-6 and TGF-ß, respectively. In this study, we generated two Th17 subpopulations by using a system in which naive CD4 cells from TCR transgenic mice specific to hen egg lysozyme (HEL) are polarized with IL-6/TGF-ß and, concurrently, are activated either with HEL presented by APCs, or with anti-CD3/CD28 Abs. Only the former cells were pathogenic, inducing inflammation in eyes expressing HEL. Naive CD4 cells activated by the anti-CD3/CD28 Abs acquired pathogenicity, however, when cocultured with HEL/APC. Importantly, the naive CD4 cells did not acquire pathogenicity when cocultured with APCs stimulated with LPS or when separated from the HEL-presenting cells by a semipermeable membrane. Unlike with presensitized Th17, soluble IL-23 does not participate in pathogenicity acquisition by naive CD4 cells; no pathogenicity was induced by adding IL-23 to cultures activated with anti-CD3/CD28 Abs. Furthermore, Abs against IL-23 or IL-23R did not inhibit acquisition of pathogenicity in cultures of naive CD4 cells activated by HEL/APC. Our data thus show that, unlike presensitized CD4 cells, naive CD4 cells polarized toward Th17 phenotype acquire pathogenicity only by direct interaction with APCs presenting the Ag, with no apparent involvement of soluble IL-23. We suggest that the Th17 lymphocytes derived from naive CD4 cells participate in pathogenic and other immune processes, along with the IL-23-dependent Th17 cells.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Comunicación Celular/inmunología , Linaje de la Célula/inmunología , Muramidasa/metabolismo , Células Th17/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/patología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Oftalmopatías/enzimología , Oftalmopatías/inmunología , Oftalmopatías/patología , Inflamación/enzimología , Inflamación/inmunología , Inflamación/patología , Interleucina-23/metabolismo , Ratones , Ratones Transgénicos , Muramidasa/efectos adversos , Muramidasa/inmunología , Células Th17/enzimología , Células Th17/patología
10.
Nat Med ; 13(6): 711-8, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17496900

RESUMEN

T-helper type 17 cells (T(H)17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-gamma. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-alpha in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.


Asunto(s)
Proliferación Celular , Inhibidores de Crecimiento/fisiología , Interleucina-2/fisiología , Interleucinas/fisiología , Factor de Transcripción STAT1/fisiología , Escleritis/patología , Linfocitos T Colaboradores-Inductores/inmunología , Uveítis/patología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Células Cultivadas , Técnicas de Cocultivo , Humanos , Interleucinas/biosíntesis , Interleucinas/genética , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Escleritis/inmunología , Escleritis/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Uveítis/inmunología , Uveítis/metabolismo
11.
Immunology ; 140(4): 475-82, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23906311

RESUMEN

DNAX-activation protein 12 (DAP12), a transmembrane adapter, plays a major role in transducing activation signals in natural killer cells and various myeloid cells. Quantitative RT-PCR detected in normal mouse eyes considerable levels of DAP12 and multiple DAP12-coupled receptors, in particular TREM-1, Clec5a and SIRPb1. The role of DAP12 and its receptors in experimental autoimmune diseases has been controversial. Here, we analysed the effect of DAP12 deficiency on the capacity of mice to mount immunopathogenic cellular responses to the uveitogenic ocular antigen and interphotoreceptor retinoid-binding protein (IRBP), and to develop experimental autoimmune uveitis (EAU). Surprisingly, sequential analysis of EAU in mice deficient in DAP12 in two different animal facilities at first revealed enhanced disease as compared with wild-type mice, but when these mice were re-derived into a second, cleaner, animal facility, the response of control mice was essentially unchanged, whereas the DAP12 null mice were markedly hyporesponsive relative to controls in the new facility. Accordingly, when stimulated in vitro with IRBP, lymphocytes from the DAP12-deficient mice housed in the two facilities proliferated and produced opposite profiles of pro-inflammatory and anti-inflammatory cytokines, compared with their controls. These findings therefore demonstrate that the effects of DAP12 deficiency on development of autoimmune disease are dramatically affected by environmental factors.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Enfermedades Autoinmunes/metabolismo , Ambiente , Ojo/metabolismo , Vivienda para Animales , Uveítis/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/prevención & control , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Ojo/inmunología , Proteínas del Ojo/metabolismo , Mediadores de Inflamación/metabolismo , Lectinas Tipo C/metabolismo , Activación de Linfocitos , Linfocitos/inmunología , Linfocitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas de Unión al Retinol/metabolismo , Receptor Activador Expresado en Células Mieloides 1 , Uveítis/genética , Uveítis/inmunología , Uveítis/prevención & control
12.
Crit Rev Immunol ; 32(1): 1-10, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22428852

RESUMEN

Although it was discovered more than two decades ago, new information concerning the biological activities of IL-9 has been provided in recent years, after the isolation of cells that selectively produce this cytokine, designated "Th9." Th9 cells are generated in vitro by polarization, mainly by TGF-ß and IL-4, during activation with the specific antigen, or with anti-CD3/CD28 antibodies. This review deals mainly with Th9 generated by the former, "physiological" mode of activation. Of particular interest is the unique production kinetics of IL-9: the cytokine is produced very rapidly, but after reaching its peak (day 3 in our studies), it declines sharply to trace levels. In addition to IL-9, Th9 cells also produce similar amounts of another cytokine, IL-10, but the production kinetics of these two cytokines are strikingly different. Antigen-activated Th9 in our studies also developed pathogenic capacity, but only during the short time period of peak IL-9 production. Interestingly, no IL-9-producing cells were detected in sites of inflammation induced by Th9, in contrast to Thl and Thl7. The unique features of Th9 cells and their products are discussed with regards to the known and assumed functions of the cytokine.


Asunto(s)
Interleucina-9/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Antígenos/inmunología , Humanos , Interleucina-9/biosíntesis , Cinética
13.
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
14.
J Immunol ; 185(11): 6795-801, 2010 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-20971929

RESUMEN

Recently reported lines of Th9 cells, producing IL-9 and IL-10, were generated by polarization with IL-4 and TGF-ß and activation with Abs against CD3 and CD28. In this paper, we analyzed features of Th9 lines similarly polarized but activated by the "natural mode" (i.e., exposure of CD4 cells to their target Ag, hen egg lysozyme [HEL] and APCs). Main observations are the following: 1) both IL-9 and IL-10 were expressed by the line cells, but with strikingly different kinetics, with IL-9 being produced rapidly, reaching a peak on day 3 in culture and declining sharply thereafter, whereas IL-10 production increased gradually, resembling IL-4 and IL-17 production by their corresponding lineage cells; 2) reactivation of Th9, following expansion, triggered faster and higher production of both IL-9 and IL-10; 3) incubating Th9 cells in polarizing media specific for other phenotypes stimulated moderate levels of phenotype switching to Th1 or Th17 but a massive switching to Th2; 4) Th9 cells induced moderate inflammation in HEL-expressing recipient eyes but only when producing high levels of IL-9; and 5) IL-9-producing donor cells were detected in the blood of Th9 recipients but not in their inflamed eyes, suggesting that similar to findings in culture, exposure to HEL in these eyes arrested the IL-9 production in Th9 cells. Collectively, these data provide new information concerning Th9 cells and reveal their uniqueness, in particular with regard to the unusual production kinetics of IL-9 and the short retention of these cells in affected target tissues.


Asunto(s)
Proteínas del Ojo/metabolismo , Mediadores de Inflamación/metabolismo , Interleucina-9/biosíntesis , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Línea Celular , Pollos , Relación Dosis-Respuesta Inmunológica , Epítopos de Linfocito T/biosíntesis , Epítopos de Linfocito T/inmunología , Proteínas del Ojo/fisiología , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/fisiología , Interleucina-10/biosíntesis , Interleucina-10/metabolismo , Interleucina-9/metabolismo , Cinética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Muramidasa/biosíntesis , Muramidasa/genética , Muramidasa/inmunología , Especificidad de Órganos/inmunología , Receptores de Antígenos de Linfocitos T/biosíntesis , Linfocitos T Colaboradores-Inductores/patología , Factores de Tiempo
16.
Cell Immunol ; 271(2): 210-3, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21903206

RESUMEN

Th1 cells are remarkably more susceptible to activation induced cell death than Th17. Here, we compared cultures of these two cell subpopulations for their expression of apoptosis-related molecules when re-exposed to their specific antigen. We also compared the expression of apoptosis-related molecules in the mouse eye with inflammation induced by Th1 or Th17 cells. Using qPCR we found that the mRNA transcript levels of the majority of tested apoptosis-related molecules were higher in the Th1 cultures, and in eyes with Th1-induced inflammation. Apoptotic intrinsic pathway molecules played minor roles in the processes in vitro or in vivo, whereas extrinsic pathway molecules, as well as PD-1, its ligands and Tim3, were heavily involved.


Asunto(s)
Apoptosis/inmunología , Células TH1/inmunología , Células TH1/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Traslado Adoptivo , Animales , Línea Celular , Oftalmopatías/etiología , Oftalmopatías/inmunología , Inflamación/etiología , Inflamación/inmunología , Activación de Linfocitos , Ratones , Ratones Transgénicos
17.
J Immunol ; 183(11): 7547-56, 2009 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19890052

RESUMEN

Both Th1 and Th17 T cell subsets can mediate inflammation, but the kinetics of the pathogenic processes mediated by these two subsets have not been investigated. Using an experimental system in which TCR-transgenic Th1 or Th17 cells specific for hen egg lysozyme induce ocular inflammation in recipient mice expressing eye-restricted hen egg lysozyme, we found important differences in the in vivo behavior of these two subsets. Th1 cells initially proliferated considerably faster and invaded the eye more quickly than their Th17 counterparts, but then disappeared rapidly. By contrast, Th17 cells accumulated and remained the majority of the infiltrating CD4(+) cells in the eye for as long as 25 days after transfer, mediating more long-lasting pathological changes. Unlike Th1, Th17 cells were highly resistant to restimulation-induced apoptosis, a major pathway by which autoimmune and chronically restimulated Th1 cells are eliminated. Th17 cells had reduced Fas ligand production and resistance to Fas-induced apoptosis, relative to Th1 cells, despite similar surface expression of Fas. Th17-induced ocular inflammation also differed from Th1-induced inflammation by consisting of more neutrophils, whereas Th1-induced disease had higher proportions of CD8 cells. Taken together, our data show that pathogenic processes triggered by Th17 lag behind those induced by Th1, but then persist remarkably longer, apparently due to the relative resistance of Th17 cells to restimulation-induced cell death. The long-lasting inflammation induced by Th17 cells is in accord with these cells being involved in chronic conditions in humans.


Asunto(s)
Apoptosis/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Inflamación/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos , División Celular , Ojo/inmunología , Proteína Ligando Fas/inmunología , Proteína Ligando Fas/metabolismo , Citometría de Flujo , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Ratones , Ratones Transgénicos , Muramidasa/inmunología , Células TH1/inmunología , Receptor fas/inmunología , Receptor fas/metabolismo
18.
J Immunol ; 181(10): 7205-13, 2008 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-18981142

RESUMEN

Th1 and Th17 cells are characterized by their expression of IFN-gamma or IL-17, respectively. The finding of Th cells producing both IL-17 and IFN-gamma suggested, however, that certain Th cells may modify their selective cytokine expression. In this study, we examined changes in cytokine expression in an experimental system in which polarized Th1 or Th17 cells specific against hen egg lysozyme induce ocular inflammation in recipient mice expressing hen egg lysozyme in their eyes. Whereas only IFN-gamma was expressed in eyes of Th1 recipient mice, substantial proportions of donor cells expressed IFN-gamma or both IFN-gamma and IL-17 in Th17 recipient eyes. The possibility that nonpolarized cells in Th17 preparations were responsible for expression of IFN-gamma or IFN-gamma/IL-17 in Th17 recipient eyes was contradicted by the finding that the proportions of such cells were larger in recipients of Th17 preparations with 20-25% nonpolarized cells than in recipients of 35-40% preparations. Moreover, whereas incubation in vitro of Th1 cells with Th17-polarizing mixture had no effect on their phenotype, incubation of Th17 with Th1-polarizing mixture, or in the absence of cytokines, converted most of these cells into IFN-gamma or IFN-gamma/IL-17-expressing cells. In addition, Th17 incubated with the Th1 mixture expressed T-bet, whereas no ROR-gamma t was detected in Th1 incubated with Th17 mixture. Thus, polarized Th1 cells retain their phenotype in the tested systems, whereas Th17 may switch to express IFN-gamma or IFN-gamma/IL-17 following activation in the absence of cytokines, or exposure to certain cytokine milieus at the inflammation site or in culture.


Asunto(s)
Inflamación/inmunología , Interferón gamma/biosíntesis , Interleucina-17/biosíntesis , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Animales , Oftalmopatías/inmunología , Oftalmopatías/metabolismo , Citometría de Flujo , Inmunofenotipificación , Inflamación/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Muramidasa/inmunología , Fenotipo , Receptores de Antígenos de Linfocitos T/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/metabolismo , Células TH1/metabolismo
19.
Front Immunol ; 11: 583510, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33569048

RESUMEN

Non-infectious uveitis, a common cause of blindness in man, is often mediated by autoimmunity, a process in which cytokines play major roles. The biosynthesis and secretion of pro-inflammatory cytokines are regulated in part by tristetraprolin (TTP), an endogenous anti-inflammatory protein that acts by binding directly to specific sequence motifs in the 3'-untranslated regions of target mRNAs, promoting their turnover, and inhibiting synthesis of their encoded proteins. We recently developed a TTP-overexpressing mouse (TTPΔARE) by deleting an AU-rich element (ARE) instability motif from the TTP mRNA, resulting in increased accumulation of TTP mRNA and protein throughout the animal. Here, we show that homozygous TTPΔARE mice are resistant to the induction of experimental autoimmune uveitis (EAU) induced by interphotoreceptor retinoid-binding protein (IRBP), an established model for human autoimmune (noninfectious) uveitis. Lymphocytes from TTPΔARE mice produced lower levels of the pro-inflammatory cytokines IFN-γ, IL-17, IL-6, and TNFα than wild type (WT) mice. TTPΔARE mice also produced lower titers of antibodies against the uveitogenic protein. In contrast, TTPΔARE mice produced higher levels of the anti-inflammatory cytokine IL-10, and had higher frequencies of regulatory T-cells, which, moreover, displayed a moderately higher per-cell regulatory ability. Heterozygous mice developed EAU and associated immunological responses at levels intermediate between homozygous TTPΔARE mice and WT controls. TTPΔARE mice were able, however, to develop EAU following adoptive transfer of activated WT T-cells specific to IRBP peptide 651-670, and naïve T-cells from TTPΔARE mice could be activated by antibodies to CD3/CD28. Importantly, TTPΔARE antigen presenting cells were significantly less efficient compared to WT in priming naïve T cells, suggesting that this feature plays a major role in the dampened immune responses of the TTPΔARE mice. Our observations demonstrate that elevated systemic levels of TTP can inhibit the pathogenic processes involved in EAU, and suggest the possible use of TTP-based treatments in humans with uveitis and other autoimmune conditions.


Asunto(s)
Enfermedades Autoinmunes/metabolismo , Enfermedad Autoinmune Experimental del Sistema Nervioso/metabolismo , Tristetraprolina/metabolismo , Uveítis/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Femenino , Técnicas de Sustitución del Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad Autoinmune Experimental del Sistema Nervioso/inmunología , Enfermedad Autoinmune Experimental del Sistema Nervioso/patología , Tristetraprolina/inmunología , Uveítis/inmunología , Uveítis/patología
20.
Cell Rep ; 28(2): 486-497.e4, 2019 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-31291583

RESUMEN

Type I interferons (IFNs) have therapeutic potential in CNS autoimmune diseases, such as uveitis, but the molecular mechanisms remain unclear. Using a T cell-transfer model of experimental autoimmune uveitis (EAU), we found that IFN-α/ß treatment inhibited the migration of IFN-γ-producing pathogenic CD4+ T cells to effector sites. IFN-α/ß upregulated the expression of the cognate ligands CXCL9, CXCL10, and CXCL11, causing ligand-mediated downregulation of CXCR3 expression and effector T cell retention in the spleen. Accordingly, type I IFN did not alter EAU progression in CXCR3-/- mice. In uveitis patients, disease exacerbations correlated with reduced serum IFN-α concentrations. IFN-α/ß reduced CXCR3 expression and migration by human effector T cells, and these parameters were associated with the therapeutic efficacy of IFN-α in uveitis patients. Our findings provide insight into the molecular basis of type I IFN therapy for CNS autoimmune diseases and identify CXCR3 as a biomarker for effective type I IFN immunotherapy.


Asunto(s)
Enfermedades Autoinmunes/genética , Inmunoterapia/métodos , Interferón Tipo I/metabolismo , Receptores CXCR3/antagonistas & inhibidores , Linfocitos T/metabolismo , Animales , Humanos , Ratones
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