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1.
Am J Respir Crit Care Med ; 195(12): 1576-1585, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28125291

RESUMO

RATIONALE: Leukocyte recruitment to sites of allergic inflammation depends on the local production of priming cytokines, chemokines, and potentially other mediators. Previously, we showed that eosinophils (Eos) express numerous orphan G-protein-coupled receptors, including Epstein-Barr virus-induced gene 2 (EBI2). Despite its contribution to inflammatory diseases, the role of EBI2 in pulmonary eosinophilia is unknown. OBJECTIVES: To determine whether oxysterol ligands for EBI2 are increased in asthma exacerbation, and if or how they promote Eos pulmonary migration. METHODS: EBI2 ligands and pulmonary eosinophilia were measured in the bronchoalveolar lavage fluid from patients with mild asthma 48 hours after acute allergen challenge. In vitro, the ability of EBI2 ligands alone or in combination with IL-5 priming to induce the migration of human blood Eos was assessed. MEASUREMENTS AND MAIN RESULTS: EBI2 was constitutively and stably expressed in peripheral blood Eos. Eos treated with the EBI2 ligands showed significantly increased transwell migration that was enhanced by priming with physiologic doses of IL-5. Migration was suppressed by inhibitors of the prolyl isomerase Pin1 or extracellular signal-regulated kinases (ERK) 1/2 or by pertussis toxin. EBI2 signaling activated Pin1 isomerase activity through a cascade that was sensitive to ERK inhibitors and pertussis toxin. The concentration of EBI2 ligands was significantly increased in the bronchoalveolar lavage fluid 48 hours after segmental allergen challenge and strongly correlated with the increased numbers of Eos, lymphocytes, and neutrophils in the airways. CONCLUSIONS: Oxysterols are increased in inflamed airways after allergen challenge and, through G-protein subunit α, ERK, and Pin1 signaling, likely participate in the regulation of Eos migration into the lung in people with asthma.


Assuntos
Alérgenos/imunologia , Asma/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Movimento Celular , Eosinófilos/imunologia , Humanos , Contagem de Leucócitos , Transdução de Sinais/genética , Transdução de Sinais/imunologia
2.
Neurol Neuroimmunol Neuroinflamm ; 2(6): e170, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26587555

RESUMO

OBJECTIVE: To determine the antigenic determinants and specific molecular requirements for the generation of autoregulatory neuroantigen-specific CD8(+) T cells in models of multiple sclerosis (MS). METHODS: We have previously shown that MOG35-55-specific CD8(+) T cells suppress experimental autoimmune encephalomyelitis (EAE) in the C57BL/6 model. In this study, we utilized multiple models of EAE to assess the ability to generate autoregulatory CD8(+) T cells. RESULTS: We demonstrate that alternative myelin peptides (PLP178-191) and other susceptible mouse strains (SJL) generated myelin-specific CD8(+) T cells, which were fully capable of suppressing disease. The disease-ameliorating function of these cells was dependent on the specific cognate myelin antigen. Generation of these autoregulatory CD8(+) T cells was not affected by thymic selection, but was dependent on the presence of both CD4(+) and CD8(+) T-cell epitopes in the immunizing encephalitogenic antigen. CONCLUSIONS: These studies show that the generation of autoregulatory CD8(+) T cells is a more generalized, antigen-specific phenomenon across multiple neuroantigens and mouse strains, with significant implications in understanding disease regulation.

3.
Nat Rev Cancer ; 15(7): 426-39, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26105539

RESUMO

Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.


Assuntos
Rabdomiossarcoma/etiologia , Animais , Modelos Animais de Doenças , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Proteínas Hedgehog/fisiologia , Humanos , Mutação , Mioblastos/metabolismo , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Rabdomiossarcoma/genética , Rabdomiossarcoma/terapia , Células-Tronco/metabolismo , Proteínas ras/genética
4.
PLoS One ; 9(12): e114155, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25531437

RESUMO

Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat-based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T-lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross-reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines.


Assuntos
Epitopos de Linfócito T/imunologia , HIV-1/imunologia , Segurança , Linfócitos T Auxiliares-Indutores/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Antivirais/imunologia , Linhagem Celular , Engenharia , Epitopos de Linfócito B/imunologia , Espaço Extracelular/metabolismo , Feminino , Vetores Genéticos/genética , Imunização , Camundongos , Estrutura Terciária de Proteína , Células Th1/imunologia , Células Th2/imunologia , Ativação Transcricional/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/genética , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo
5.
PLoS One ; 9(8): e105763, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25144738

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model of multiple sclerosis, an immune-mediated demyelinating disorder of the central nervous system (CNS). We have previously shown that CNS-specific CD8+ T cells (CNS-CD8+) ameliorate EAE, at least in part through modulation of CNS-specific CD4+ T cell responses. In this study, we show that CNS-CD8+ also modulate the function of CD11c+ dendritic cells (DC), but not other APCs such as CD11b+ monocytes or B220+ B cells. DC from mice receiving either myelin oligodendrocyte glycoprotein-specific CD8+ (MOG-CD8+) or proteolipid protein-specific CD8+ (PLP-CD8+) T cells were rendered inefficient in priming T cell responses from naïve CD4+ T cells (OT-II) or supporting recall responses from CNS-specific CD4+ T cells. CNS-CD8+ did not alter DC subset distribution or MHC class II and CD86 expression, suggesting that DC maturation was not affected. However, the cytokine profile of DC from CNS-CD8+ recipients showed lower IL-12 and higher IL-10 production. These functions were not modulated in the absence of immunization with CD8-cognate antigen, suggesting an antigen-specific mechanism likely requiring CNS-CD8-DC interaction. Interestingly, blockade of IL-10 in vitro rescued CD4+ proliferation and in vivo expression of IL-10 was necessary for the suppression of EAE by MOG-CD8+. These studies demonstrate a complex interplay between CNS-specific CD8+ T cells, DC and pathogenic CD4+ T cells, with important implications for therapeutic interventions in this disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Animais , Autoantígenos/imunologia , Antígeno B7-2/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Antígenos de Histocompatibilidade Classe II/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Camundongos , Esclerose Múltipla/patologia
6.
J Immunol ; 191(1): 117-26, 2013 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-23733879

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS, and CD8 T cells are the predominant T cell population in MS lesions. Given that transfer of CNS-specific CD8 T cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular targets and mechanisms of autoreactive regulatory CD8 T cells. In this study we report that myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced CD8 T cells could also attenuate adoptively transferred, CD4 T cell-mediated EAE. Whereas CD8(-/-) mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T cells, this was reversed by adoptive transfer of MOG-specific CD8 T cells. These autoregulatory CD8 T cells required in vivo MHC class Ia (K(b)D(b)) presentation. Interestingly, MOG-specific CD8 T cells could also suppress adoptively induced disease using wild-type MOG35-55-specific CD4 T cells transferred into K(b)D(b-/-) recipient mice, suggesting direct targeting of encephalitogenic CD4 T cells. In vivo trafficking analysis revealed that autoregulatory CD8 T cells are dependent on neuroinflammation for CNS infiltration, and their suppression/cytotoxicity of MOG-specific CD4 T cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T cells in EAE.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Transferência Adotiva , Sequência de Aminoácidos , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/prevenção & controle , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Citotoxicidade Imunológica , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular
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