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1.
Eur J Immunol ; 44(10): 2903-17, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25056715

RESUMO

The role of IFN-γ in the pathogenesis of autoimmune diseases is controversial. Although Th1 cells can induce experimental autoimmune encephalomyelitis (EAE), IFN-γ can suppress Th17 cells that are pathogenic in EAE. Here we show that NK cells provide an early source of IFN-γ during development of EAE. Depletion of NK cells or neutralization of IFN-γ delayed the onset of EAE and was associated with reduced infiltration of IL-17(+) and GM-CSF(+) T cells into the CNS. In the passive transfer model, immune cells from myelin oligodendrocyte glycoprotein (MOG)-immunized IFN-γ(-/-) mice failed to induce EAE, despite producing IL-17 and GM-CSF. The macrophages expressed markers of M2 activation and the T cells had low very late antigen-4 (VLA-4) expression and failed to infiltrate the CNS. Addition of recombinant IFN-γ to immune cells from the IFN-γ(-/-) mice activated M1 macrophages and restored VLA-4 expression, migratory, and encephalitogenic activity of T cells. Furthermore, treatment of recipient mice with anti-VLA-4 neutralizing antibody abrogated EAE induced by transfer of T cells from WT mice. Our findings demonstrate IFN-γ-producing T cells are not required for development of EAE, but NK cell-derived IFN-γ has a key role in promoting M1 macrophage expansion and VLA-4-mediated migration of encephalitogenic T cells into the CNS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Transferência Adotiva , Animais , Quimiotaxia de Leucócito/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Citometria de Fluxo , Interferon gama/biossíntese , Células Matadoras Naturais/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T/imunologia , Linfócitos T/metabolismo
2.
Cancer Immunol Immunother ; 62(7): 1273-82, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23657628

RESUMO

The immune system has evolved regulatory mechanisms to control immune responses to self-antigens. Regulatory T (Treg) cells play a pivotal role in maintaining immune tolerance, but tumour growth is associated with local immunosuppression, which can subvert effector immune responses. Indeed, the induction and recruitment of Treg cells by tumours is a major barrier in the development of effective immunotherapeutics and vaccines against cancer. Retinoic acid (RA) has been shown to promote conversion of naïve T cells into Treg cells. This study addresses the hypothesis that blocking RA receptor alpha (RARα) may enhance the efficacy of a tumour vaccine by inhibiting the induction of Treg cells. We found that RA significantly enhanced TGF-ß-induced expression of Foxp3 on naïve and committed T cells in vitro and that this was blocked by an antagonist of RARα (RARi). In addition, RARi significantly suppressed TGF-ß and IL-10 and enhanced IL-12 production by dendritic cells (DC) in response to killed tumour cells or TLR agonists. Furthermore, RARi augmented the efficacy of an antigen-pulsed and TLR-activated DC vaccine, significantly attenuating growth of B16 tumours in vivo and enhancing survival of mice. This protective effect was associated with significant reduction in tumour-infiltrating FoxP3(+) and IL-10(+) Treg cells and a corresponding increase in tumour-infiltrating CD4(+) and CD8(+) T cells that secreted IFN-γ. Our findings demonstrate that RARα is an important target for the development of effective anti-tumour immunotherapeutics and for improving the efficacy of cancer vaccines.


Assuntos
Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Melanoma Experimental/imunologia , Receptores do Ácido Retinoico/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Aldeído Desidrogenase/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Fatores de Transcrição Forkhead/metabolismo , Imunoterapia , Interleucina-10/antagonistas & inibidores , Interleucina-12/metabolismo , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Receptor alfa de Ácido Retinoico , Tolerância a Antígenos Próprios , Fator de Crescimento Transformador beta/antagonistas & inibidores
3.
J Immunol ; 186(10): 5738-48, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21471445

RESUMO

IL-1ß plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1ß and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1ß and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1ß or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1ß and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1ß and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1ß and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Caspase 1/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/biossíntese , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Animais , Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/genética , Inibidores de Caspase , Células Dendríticas/imunologia , Interleucina-17/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Mycobacterium tuberculosis/imunologia , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Proteína 3 que Contém Domínio de Pirina da Família NLR , Reação em Cadeia da Polimerase , Receptores de Antígenos de Linfócitos T gama-delta/genética , Células Th17/imunologia
4.
Cytokine ; 56(1): 126-32, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21824786

RESUMO

The interleukin (IL)-1 cyokine family plays a vital role in inflammatory responses during infection and in autoimmune diseases. The pro-inflammatory cytokines, IL-1ß and IL-18 are members of the IL-1 family that require cleavage by caspase-1 in the inflammasome to generate the mature active cytokines. Cells of the innate immune system, including γδ T cells and invariant natural killer T (iNKT) cells respond rapidly to invading pathogens by producing inflammatory cytokines, such as IFN-γ and IL-17. IL-1ß or IL-18 in combination with IL-23 can induce IL-17 production by γδ T cells without T cell receptor (TCR) engagement. IL-1ß and IL-23 can also synergize to induce IL-17 production by iNKT cells. Furthermore, CD4+ αß effector memory T cells secrete IL-17 in response to IL-23 in combination with either IL-1ß or IL-18, in the absence of any TCR stimulation. The early IL-17 produced by innate cells induces recruitment of neutrophils to the site of infection, stimulates local epithelial cells to secrete anti-microbial proteins, such as lipocalins and calgranulins, induces production of structural proteins important in tight junction stability, and promotes production of matrix metalloproteinases. Caspase-1 processed IL-1 family cytokines therefore play a vital role in the innate immune response and induction of IL-17 from innate immune cells which functions to fight infections and promote autoimmunity.


Assuntos
Caspase 1/metabolismo , Imunidade Inata/imunologia , Interleucina-17/imunologia , Interleucina-1/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Animais , Humanos , Receptores de Interleucina-1/imunologia
5.
Brain Behav Immun ; 25(6): 1170-81, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21420486

RESUMO

Interferon (IFN)-ß is a commonly used therapy for relapsing remitting multiple sclerosis (RRMS). However its protective mechanism is still unclear and the failure of many patients to respond has not been explained. We have found that IFN-ß suppressed IL-23 and IL-1ß production and increased IL-10 production by human dendritic cells (DC) activated with the TLR2 and dectin-1 agonist zymosan. Furthermore, IFN-ß impaired the ability of DC to promote IL-17 production by CD4(+) T cells, but did not affect IFN-γ production. IFN-ß induced IL-27 expression by DC, and neutralisation of IL-27 abrogated the suppressive effects of IFN-ß on zymosan-induced IL-1 and IL-23 production and the generation of Th17 cells in vitro. Complementary in vivo studies in a mouse model showed that treatment with IFN-ß enhanced expression of IL-27, and reduced IL-17 in the CNS and periphery and attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE). In addition, the significant suppressive effect of IFN-ß on the ability of DC to promote Th17 cells was lost in cells from IL-27 receptor deficient mice. Finally, we showed that PBMC from non-responder RRMS patients produced significantly less IL-27 in response to IFN-ß than patients who responded to IFN-ß therapy. Our findings suggest that IFN-ß mediates its therapeutic effects in MS at least in part via the induction of IL-27, and that IL-27 may represent an alternative therapy for MS patients that do not respond to IFN-ß.


Assuntos
Interferon beta/uso terapêutico , Interleucinas/fisiologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Células Th17/efeitos dos fármacos , Adulto , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Células Cultivadas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon beta-1a , Interferon beta-1b , Interferon-alfa/deficiência , Interferon-alfa/genética , Interferon beta/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/biossíntese , Interleucinas/genética , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Células Th17/imunologia , Receptores Toll-Like/efeitos dos fármacos , Receptores Toll-Like/fisiologia , Adulto Jovem , Zimosan/farmacologia
6.
Nat Med ; 21(3): 248-55, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25686105

RESUMO

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1ß (IL-1ß) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inflamassomos/antagonistas & inibidores , Interleucina-1beta/efeitos dos fármacos , Esclerose Múltipla , Sulfonas/uso terapêutico , Animais , Modelos Animais de Doenças , Furanos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Indenos , Inflamação , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfonamidas , Sulfonas/farmacologia
7.
J Leukoc Biol ; 93(4): 489-97, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23271701

RESUMO

NLRs are members of the PRR family that sense microbial pathogens and mediate host innate immune responses to infection. Certain NLRs can assemble into a multiprotein complex called the inflammasome, which activates casapse-1 required for the cleavage of immature forms of IL-1ß and IL-18 into active, mature cytokines. The inflammasome is activated by conserved, exogenous molecules from microbes and nonmicrobial molecules, such as asbestos, alum, or silica, as well as by endogenous danger signals, such as ATP, amyloid-ß, and sodium urate crystals. Activation of the inflammasome is a critical event triggering IL-1-driven inflammation and is central to the pathology of autoinflammatory diseases, such as gout and MWS. Recent studies have also shown IL-1 or IL-18, in synergy with IL-23, can promote IL-17-prduction from Th17 cells and γδ T cells, and this process can be regulated by autophagy. IL-1-driven IL-17 production plays a critical role in host protective immunity to infection with fungi, bacteria, and certain viruses. However, Th17 cells and IL-17-seceting γδ T cells, activated by inflammasome-derived IL-1 or IL-18, have major pathogenic roles in many autoimmune diseases. Consequently, inflammasomes are now major drug targets for many autoimmune and chronic inflammatory diseases, as well as autoinflammatory diseases.


Assuntos
Antígenos de Bactérias/imunologia , Imunidade Inata , Inflamassomos/imunologia , Interleucina-17/imunologia , Interleucina-1/imunologia , Células Th17/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Bactérias , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Caspases/genética , Caspases/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Interleucina-1/genética , Interleucina-17/genética , Interleucina-18/genética , Interleucina-18/imunologia , Material Particulado/imunologia , Transdução de Sinais/imunologia , Células Th17/patologia
8.
J Exp Med ; 210(6): 1117-24, 2013 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-23690441

RESUMO

Retinoic acid (RA), a vitamin A metabolite, modulates mucosal T helper cell responses. Here we examined the role of RA in regulating IL-22 production by γδ T cells and innate lymphoid cells in intestinal inflammation. RA significantly enhanced IL-22 production by γδ T cells stimulated in vitro with IL-1ß or IL-18 and IL-23. In vivo RA attenuated colon inflammation induced by dextran sodium sulfate treatment or Citrobacter rodentium infection. This was associated with a significant increase in IL-22 secretion by γδ T cells and innate lymphoid cells. In addition, RA treatment enhanced production of the IL-22-responsive antimicrobial peptides Reg3ß and Reg3γ in the colon. The attenuating effects of RA on colitis were reversed by treatment with an anti-IL-22 neutralizing antibody, demonstrating that RA mediates protection by enhancing IL-22 production. To define the molecular events involved, we used chromatin immunoprecipitation assays and found that RA promoted binding of RA receptor to the IL-22 promoter in γδ T cells. Our findings provide novel insights into the molecular events controlling IL-22 transcription and suggest that one key outcome of RA signaling may be to shape early intestinal immune responses by promoting IL-22 synthesis by γδ T cells and innate lymphoid cells.


Assuntos
Colo/imunologia , Inflamação/imunologia , Interleucinas/imunologia , Linfócitos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Tretinoína/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Citrobacter rodentium/imunologia , Colite/genética , Colite/imunologia , Colo/metabolismo , Sulfato de Dextrana/efeitos adversos , Infecções por Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Inflamação/genética , Inflamação/metabolismo , Interleucinas/biossíntese , Interleucinas/genética , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/genética , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores do Ácido Retinoico/imunologia , Receptores do Ácido Retinoico/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Transcrição Gênica/genética , Transcrição Gênica/imunologia , Tretinoína/metabolismo , Interleucina 22
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