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2.
J Immunol ; 202(4): 1153-1162, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642979

RESUMO

Endothelial dysfunction and vascular leak, pathogenic hallmarks of severe dengue disease, are directly triggered by dengue virus (DENV) nonstructural protein 1 (NS1). Previous studies have shown that immunization with NS1, as well as passive transfer of NS1-immune serum or anti-NS1 mAb, prevent NS1-mediated lethality in vivo. In this study, we evaluated the immunogenicity and protective capacity of recombinant DENV NS1 administered with cyclic dinucleotides (CDNs), potent activators of innate immune pathways and highly immunogenic adjuvants. Using both wild-type C57BL/6 mice and IFN-α/ß receptor-deficient mice, we show that NS1-CDN immunizations elicit serotype-specific and cross-reactive Ab and T cell responses. Furthermore, NS1-CDN vaccinations conferred significant homotypic and heterotypic protection from DENV2-induced morbidity and mortality. In addition, we demonstrate that high anti-NS1 Ab titers are associated with protection, supporting the role of humoral responses against DENV NS1 as correlates of protection. These findings highlight the potential of CDN-based adjuvants for inducing Ab and T cell responses and validate NS1 as an important candidate for dengue vaccine development.


Assuntos
Adjuvantes Imunológicos , Anticorpos Antivirais/imunologia , Vírus da Dengue/imunologia , Nucleotídeos Cíclicos/imunologia , Linfócitos T/imunologia , Proteínas não Estruturais Virais/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
3.
Cell Rep ; 25(11): 3074-3085.e5, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30540940

RESUMO

Intratumoral (IT) STING activation results in tumor regression in preclinical models, yet factors dictating the balance between innate and adaptive anti-tumor immunity are unclear. Here, clinical candidate STING agonist ADU-S100 (S100) is used in an IT dosing regimen optimized for adaptive immunity to uncover requirements for a T cell-driven response compatible with checkpoint inhibitors (CPIs). In contrast to high-dose tumor ablative regimens that result in systemic S100 distribution, low-dose immunogenic regimens induce local activation of tumor-specific CD8+ effector T cells that are responsible for durable anti-tumor immunity and can be enhanced with CPIs. Both hematopoietic cell STING expression and signaling through IFNAR are required for tumor-specific T cell activation, and in the context of optimized T cell responses, TNFα is dispensable for tumor control. In a poorly immunogenic model, S100 combined with CPIs generates a survival benefit and durable protection. These results provide fundamental mechanistic insights into STING-induced anti-tumor immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Animais , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Relação Dose-Resposta Imunológica , Resistencia a Medicamentos Antineoplásicos , Hematopoese , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Receptor de Morte Celular Programada 1/metabolismo , Proteínas S100/administração & dosagem , Proteínas S100/imunologia
4.
Cancer Immunol Res ; 6(4): 422-433, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29472271

RESUMO

The cGAS-STING cytosolic DNA sensing pathway may play an integral role in the initiation of antitumor immune responses. Studies evaluating the immunogenicity of various cyclic dinucleotide (CDN) STING agonists administered by intratumoral (i.t.) injection showed potent induction of inflammation, tumor necrosis, and, in some cases, durable tumor-specific adaptive immunity. However, the specific immune mechanisms underlying these responses remain incompletely defined. The majority of these studies have focused on the effect of CDNs on immune cells but have not conclusively interrogated the role of stromal cells in the acute rejection of the CDN-injected tumor. Here, we revealed a mechanism of STING agonist-mediated tumor response that relied on both stromal and immune cells to achieve tumor regression and clearance. Using knockout and bone marrow chimeric mice, we showed that although bone marrow-derived TNFα was necessary for CDN-induced necrosis, STING signaling in radioresistant stromal cells was also essential for CDN-mediated tumor rejection. These results provide evidence for crosstalk between stromal and hematopoietic cells during CDN-mediated tumor collapse after i.t. administration. These mechanistic insights may prove critical in the clinical development of STING agonists. Cancer Immunol Res; 6(4); 422-33. ©2018 AACR.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Membrana/agonistas , Neoplasias/etiologia , Neoplasias/metabolismo , Nucleotídeos Cíclicos/farmacologia , Tolerância a Radiação , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Medula Óssea/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imunidade Inata , Interferon beta/metabolismo , Melanoma Experimental , Camundongos , Camundongos Knockout , Necrose/metabolismo , Necrose/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos , Células Estromais/patologia , Células Estromais/efeitos da radiação , Carga Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
5.
Cell ; 165(4): 827-41, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27153495

RESUMO

To maintain a symbiotic relationship between the host and its resident intestinal microbiota, appropriate mucosal T cell responses to commensal antigens must be established. Mice acquire both IgG and IgA maternally; the former has primarily been implicated in passive immunity to pathogens while the latter mediates host-commensal mutualism. Here, we report the surprising observation that mice generate T cell-independent and largely Toll-like receptor (TLR)-dependent IgG2b and IgG3 antibody responses against their gut microbiota. We demonstrate that maternal acquisition of these antibodies dampens mucosal T follicular helper responses and subsequent germinal center B cell responses following birth. This work reveals a feedback loop whereby T cell-independent, TLR-dependent antibodies limit mucosal adaptive immune responses to newly acquired commensal antigens and uncovers a broader function for maternal IgG.


Assuntos
Animais Recém-Nascidos/imunologia , Microbioma Gastrointestinal , Imunidade nas Mucosas , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Leite Humano/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Animais Recém-Nascidos/microbiologia , Linfócitos B/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Receptores Toll-Like/imunologia
6.
Cell Host Microbe ; 15(2): 203-13, 2014 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-24528866

RESUMO

Pathogens utilize features of the host response as cues to regulate virulence gene expression. Salmonella enterica serovar Typhimurium (ST) sense Toll-like receptor (TLR)-dependent signals to induce Salmonella Pathogenicity Island 2 (SPI2), a locus required for intracellular replication. To examine pathogenicity in the absence of such cues, we evaluated ST virulence in mice lacking all TLR function (Tlr2(-/-)xTlr4(-/-)xUnc93b1(3d/3d)). When delivered systemically to TLR-deficient mice, ST do not require SPI2 and maintain virulence by replicating extracellularly. In contrast, SPI2 mutant ST are highly attenuated after oral infection of the same mice, revealing a role for SPI2 in the earliest stages of infection, even when intracellular replication is not required. This early requirement for SPI2 is abolished in MyD88(-/-)xTRIF(-/-) mice lacking both TLR- and other MyD88-dependent signaling pathways, a potential consequence of compromised intestinal permeability. These results demonstrate how pathogens use plasticity in virulence strategies to respond to different host immune environments.


Assuntos
Interações Hospedeiro-Patógeno , Imunidade Inata , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Transdução de Sinais , Receptores Toll-Like/imunologia , Animais , Camundongos , Camundongos Knockout , Receptores Toll-Like/deficiência , Virulência
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