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1.
Immunity ; 57(4): 772-789, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38599170

RESUMO

Adjuvants play pivotal roles in vaccine development, enhancing immunization efficacy through prolonged retention and sustained release of antigen, lymph node targeting, and regulation of dendritic cell activation. Adjuvant-induced activation of innate immunity is achieved via diverse mechanisms: for example, adjuvants can serve as direct ligands for pathogen recognition receptors or as inducers of cell stress and death, leading to the release of immunostimulatory-damage-associated molecular patterns. Adjuvant systems increasingly stimulate multiple innate pathways to induce greater potency. Increased understanding of the principles dictating adjuvant-induced innate immunity will subsequently lead to programming specific types of adaptive immune responses. This tailored optimization is fundamental to next-generation vaccines capable of inducing robust and sustained adaptive immune memory across different cohorts.


Assuntos
Adjuvantes de Vacinas , Vacinas , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Imunidade Inata , Vacinação
2.
Immunity ; 54(12): 2695-2697, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34910938

RESUMO

Adjuvants can be incorporated into vaccines to enhance the magnitude and functionality of adaptive immune responses. In this issue of Immunity, Alameh et al. (2021) reveal that lipid nanoparticles, which are key components of effective SARS-CoV-2 mRNA vaccines, have broad adjuvant function, enhancing B cell responses and protective efficacy of protein-based subunit in addition to mRNA antigens.


Assuntos
COVID-19 , Adjuvantes Imunológicos , Humanos , Lipossomos , Nanopartículas , SARS-CoV-2 , Vacinas de mRNA
3.
Immunity ; 50(6): 1412-1424.e6, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31076360

RESUMO

Assembly of inflammasomes after infection or injury leads to the release of interleukin-1ß (IL-1ß) and to pyroptosis. After inflammasome activation, cells either pyroptose or enter a hyperactivated state defined by IL-1ß secretion without cell death, but what controls these different outcomes is unknown. Here, we show that removal of the Toll-IL-1R protein SARM from macrophages uncouples inflammasome-dependent cytokine release and pyroptosis, whereby cells displayed increased IL-1ß production but reduced pyroptosis. Correspondingly, increasing SARM in cells caused less IL-1ß release and more pyroptosis. SARM suppressed IL-1ß by directly restraining the NLRP3 inflammasome and, hence, caspase-1 activation. Consistent with a role for SARM in pyroptosis, Sarm1-/- mice were protected from lipopolysaccharide (LPS)-stimulated sepsis. Pyroptosis-inducing, but not hyperactivating, NLRP3 stimulants caused SARM-dependent mitochondrial depolarization. Thus, SARM-dependent mitochondrial depolarization distinguishes NLRP3 activators that cause pyroptosis from those that do not, and SARM modulation represents a cell-intrinsic mechanism to regulate cell fate after inflammasome activation.


Assuntos
Proteínas do Domínio Armadillo/metabolismo , Citocinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Inflamassomos/metabolismo , Animais , Proteínas do Domínio Armadillo/genética , Biomarcadores , Sobrevivência Celular , Proteínas do Citoesqueleto/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ligação Proteica , Piroptose , Transdução de Sinais
4.
Eur J Immunol ; 54(2): e2350512, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37994660

RESUMO

Vaccination is considered one of the major milestones in modern medicine, facilitating the control and eradication of life-threatening infectious diseases. Vaccine adjuvants are a key component of many vaccines, serving to steer antigen-specific immune responses and increase their magnitude. Despite major advances in the field of adjuvant research over recent decades, our understanding of their mechanism of action remains incomplete. This hinders our capacity to further improve these adjuvant technologies, so addressing how adjuvants induce and control the induction of innate and adaptive immunity is a priority. Investigating how adjuvant physicochemical properties, such as size and charge, exert immunomodulatory effects can provide valuable insights and serve as the foundation for the rational design of vaccine adjuvants. Most clinically applied adjuvants are particulate in nature and polymeric particulate adjuvants present advantages due to stability, biocompatibility profiles, and flexibility in terms of formulation. These properties can impact on antigen release kinetics and biodistribution, cellular uptake and targeting, and drainage to the lymphatics, consequently dictating the induction of innate, cellular, and humoral adaptive immunity. A current focus is to apply rational design principles to the development of adjuvants capable of eliciting robust cellular immune responses including CD8+ cytotoxic T-cell and Th1-biased CD4+ T-cell responses, which are required for vaccines against intracellular pathogens and cancer. This review highlights recent advances in our understanding of how particulate adjuvants, especially polymer-based particulates, modulate immune responses and how this can be used as a guide for improved adjuvant design.


Assuntos
Adjuvantes de Vacinas , Vacinas , Distribuição Tecidual , Vacinação , Imunidade Adaptativa , Adjuvantes Imunológicos/farmacologia , Antígenos
5.
Immunity ; 44(3): 597-608, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26944200

RESUMO

The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Quitosana/administração & dosagem , Células Dendríticas/fisiologia , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Nucleotidiltransferases/metabolismo , Células Th1/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Movimento Celular , Células Cultivadas , DNA/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/genética , Imunoglobulina G/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Nucleotidiltransferases/genética , Espécies Reativas de Oxigênio/metabolismo , Vacinas/administração & dosagem
6.
Immunity ; 44(2): 368-79, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26885859

RESUMO

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.


Assuntos
Interferon gama/metabolismo , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Mycobacterium tuberculosis/imunologia , Receptores de Interleucina-1/metabolismo , Tuberculose Pulmonar/imunologia , Animais , Autofagia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Células HEK293 , Humanos , Imunidade Inata/genética , Sistema de Sinalização das MAP Quinases/genética , Macrófagos/microbiologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Polimorfismo Genético , Ligação Proteica/genética , RNA Interferente Pequeno/genética , Receptores de Interferon/metabolismo , Receptores de Interleucina-1/genética , Tuberculose Pulmonar/genética , Receptor de Interferon gama
7.
Semin Immunol ; 56: 101542, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34973890

RESUMO

The dogma that immunological memory is an exclusive trait of adaptive immunity has been recently challenged by studies showing that priming of innate cells can also result in modified long-term responsiveness to secondary stimuli, once the cells have returned to a non-activated state. This phenomenon is known as 'innate immune memory', 'trained immunity' or 'innate training'. While the main known triggers of trained immunity are microbial-derived molecules such as ß-glucan, endogenous particles such as oxidized low-density lipoprotein and monosodium urate crystals can also induce trained phenotypes in innate cells. Whether exogenous particles can induce trained immunity has been overlooked. Our exposure to particulates has dramatically increased in recent decades as a result of the broad medical use of particle-based drug carriers, theragnostics, adjuvants, prosthetics and an increase in environmental pollution. We recently showed that pristine graphene can induce trained immunity in macrophages, enhancing their inflammatory response to TLR agonists, proving that exogenous nanomaterials can affect the long-term response of innate cells. The consequences of trained immunity can be beneficial, for instance, enhancing protection against unrelated pathogens; however, they can also be deleterious if they enhance inflammatory disorders. Therefore, studying the ability of particulates and biomaterials to induce innate trained phenotypes in cells is warranted. Here we analyse the mechanisms whereby particles can induce trained immunity and discuss how physicochemical characteristics of particulates could influence the induction of innate memory. We review the implications of trained immunity in the context of particulate adjuvants, nanocarriers and nanovaccines and their potential applications in medicine. Finally, we reflect on the unanswered questions and the future of the field.


Assuntos
Imunidade Inata , Nanopartículas , Imunidade Adaptativa , Adjuvantes Imunológicos , Humanos , Memória Imunológica , Macrófagos
8.
Immunol Rev ; 296(1): 169-190, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32594569

RESUMO

Therapeutic vaccination offers great promise as an intervention for a diversity of infectious and non-infectious conditions. Given that most chronic health conditions are thought to have an immune component, vaccination can at least in principle be proposed as a therapeutic strategy. Understanding the nature of protective immunity is of vital importance, and the progress made in recent years in defining the nature of pathological and protective immunity for a range of diseases has provided an impetus to devise strategies to promote such responses in a targeted manner. However, in many cases, limited progress has been made in clinical adoption of such approaches. This in part results from a lack of safe and effective vaccine adjuvants that can be used to promote protective immunity and/or reduce deleterious immune responses. Although somewhat simplistic, it is possible to divide therapeutic vaccine approaches into those targeting conditions where antibody responses can mediate protection and those where the principal focus is the promotion of effector and memory cellular immunity or the reduction of damaging cellular immune responses as in the case of autoimmune diseases. Clearly, in all cases of antigen-specific immunotherapy, the identification of protective antigens is a vital first step. There are many challenges to developing therapeutic vaccines beyond those associated with prophylactic diseases including the ongoing immune responses in patients, patient heterogeneity, and diversity in the type and stage of disease. If reproducible biomarkers can be defined, these could allow earlier diagnosis and intervention and likely increase therapeutic vaccine efficacy. Current immunomodulatory approaches related to adoptive cell transfers or passive antibody therapy are showing great promise, but these are outside the scope of this review which will focus on the potential for adjuvanted therapeutic active vaccination strategies.


Assuntos
Adjuvantes Imunológicos , Imunomodulação , Vacinação , Vacinas/imunologia , Vacinas/uso terapêutico , Animais , Formação de Anticorpos/imunologia , Autoimunidade , Gerenciamento Clínico , Humanos , Imunidade Celular , Imunidade Humoral , Terapia de Alvo Molecular , Resultado do Tratamento , Vacinação/métodos , Vacinas/administração & dosagem
9.
Nat Immunol ; 11(10): 897-904, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20835230

RESUMO

Interleukin 1ß (IL-1ß) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1ß. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1ß production in vitro. Processing of IL-1ß initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1ß in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.


Assuntos
Amiloide/metabolismo , Proteínas de Transporte/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Interleucina-1beta/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glibureto/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Ilhotas Pancreáticas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/genética
10.
Eur J Immunol ; 50(7): 932-938, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32438473

RESUMO

The recent outbreak of coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses an enormous threat to global public health and economies. Human coronaviruses normally cause no or mild respiratory disease but in the past two decades, potentially fatal coronavirus infections have emerged, causing respiratory tract illnesses such as pneumonia and bronchitis. These include severe acute respiratory syndrome coronavirus (SARS-CoV), followed by the Middle East respiratory syndrome coronavirus (MERS-CoV), and recently the SARS-CoV-2 coronavirus outbreak that emerged in Wuhan, China, in December 2019. Currently, most COVID-19 patients receive traditional supportive care including breathing assistance. To halt the ongoing spread of the pandemic SARS-CoV-2 coronavirus and rescue individual patients, established drugs and new therapies are under evaluation. Since it will be some time until a safe and effective vaccine will be available, the immediate priority is to harness innate immunity to accelerate early antiviral immune responses. Second, since excessive inflammation is a major cause of pathology, targeted anti-inflammatory responses are being evaluated to reduce inflammation-induced damage to the respiratory tract and cytokine storms. Here, we highlight prominent immunotherapies at various stages of development that aim for augmented anti-coronavirus immunity and reduction of pathological inflammation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Imunidade Inata/efeitos dos fármacos , Imunoterapia/métodos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Animais , Anti-Inflamatórios/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Humanos , Imunização Passiva , Imunomodulação , Pandemias/prevenção & controle , Pneumonia Viral/patologia , Pneumonia Viral/prevenção & controle , SARS-CoV-2 , Soroterapia para COVID-19
11.
J Immunol ; 202(4): 1145-1152, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30642984

RESUMO

The cytokine IL-33 is a well-established inducer of Th2 responses. However, roles for IL-33 in promoting CD8, Th1, and T regulatory cell responses have also emerged. In this study, the role of IL-33 as a regulator of particulate vaccine adjuvant-induced Ag-specific cellular immunity was investigated. We found that polymeric nanoparticles surpassed alum in their ability to enhance Ag-specific CD8 and Th1 responses. IL-33 was a potent negative regulator of both CD8+ T cell and Th1 responses following i.m. vaccination with Ag and nanoparticles, whereas the cytokine was required for the nanoparticle enhancement in Ag-specific IL-10. In contrast to the effect on cellular immunity, Ab responses were comparable between vaccinated wild-type and IL-33-deficient mice. IL-33 did not compromise alum-induced adaptive cellular immunity after i.m. vaccination. These data suggest that IL-33 attenuates the induction of cellular immune responses by nanoparticulate adjuvants and should be considered in the rational design of vaccines targeting enhanced CD8 and Th1 responses.


Assuntos
Antígenos/imunologia , Imunidade Celular/imunologia , Interleucina-33/imunologia , Vacinas/imunologia , Animais , Antígenos/administração & dosagem , Injeções Intramusculares , Interleucina-33/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nanopartículas/administração & dosagem , Nanopartículas/química , Vacinação , Vacinas/administração & dosagem
12.
Mol Cell ; 49(6): 1034-48, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23434371

RESUMO

Apoptosis is commonly thought to represent an immunologically silent or even anti-inflammatory mode of cell death, resulting in cell clearance in the absence of explicit activation of the immune system. However, here we show that Fas/CD95-induced apoptosis is associated with the production of an array of cytokines and chemokines, including IL-6, IL-8, CXCL1, MCP-1, and GMCSF. Fas-induced production of MCP-1 and IL-8 promoted chemotaxis of phagocytes toward apoptotic cells, suggesting that these factors serve as "find-me" signals in this context. We also show that RIPK1 and IAPs are required for optimal production of cytokines and chemokines in response to Fas receptor stimulation. Consequently, a synthetic IAP antagonist potently suppressed Fas-dependent expression of multiple proinflammatory mediators and inhibited Fas-induced chemotaxis. Thus, in addition to provoking apoptosis, Fas receptor stimulation can trigger the secretion of chemotactic factors and other immunologically active proteins that can influence immune responsiveness toward dying cells.


Assuntos
Apoptose , Quimiocina CCL2/fisiologia , Interleucina-8/fisiologia , Receptor fas/fisiologia , Animais , Caspase 8/metabolismo , Quimiocina CCL2/metabolismo , Quimiocinas/metabolismo , Quimiocinas/fisiologia , Quimiotaxia , Regulação da Expressão Gênica , Células HeLa , Humanos , Mediadores da Inflamação/metabolismo , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/metabolismo , Interleucina-8/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fagócitos/fisiologia , Ligação Proteica , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , Receptor fas/metabolismo
13.
J Allergy Clin Immunol ; 145(4): 1272-1284.e6, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31983527

RESUMO

BACKGROUND: The World Health Organization estimates that air pollution is responsible for 7 million deaths per annum, with 7% of these attributable to pneumonia. Many of these fatalities have been linked to exposure to high levels of airborne particulates, such as diesel exhaust particles (DEPs). OBJECTIVES: We sought to determine whether exposure to DEPs could promote the progression of asymptomatic nasopharyngeal carriage of Streptococcus pneumoniae to invasive pneumococcal disease. METHODS: We used mouse models and in vitro assays to provide a mechanistic understanding of the link between DEP exposure and pneumococcal disease risk, and we confirmed our findings by using induced sputum macrophages isolated from healthy human volunteers. RESULTS: We demonstrate that inhaled exposure to DEPs disrupts asymptomatic nasopharyngeal carriage of S pneumoniae in mice, leading to dissemination to lungs and blood. Pneumococci are transported from the nasopharynx to the lungs following exposure to DEPs, leading to increased proinflammatory cytokine production, reduced phagocytic function of alveolar macrophages, and consequently, increased pneumococcal loads within the lungs and translocation into blood. These findings were confirmed by using DEP-exposed induced sputum macrophages isolated from healthy volunteers, demonstrating that impaired innate immune mechanisms following DEP exposure are also at play in humans. CONCLUSION: Lung inhaled DEPs increase susceptibility to pneumococcal disease by leading to loss of immunological control of pneumococcal colonisation, increased inflammation, tissue damage, and systemic bacterial dissemination.


Assuntos
Pulmão/imunologia , Macrófagos/imunologia , Nasofaringe/patologia , Material Particulado/efeitos adversos , Pneumonia Pneumocócica/imunologia , Streptococcus pneumoniae/fisiologia , Animais , Bacteriemia , Portador Sadio , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Suscetibilidade a Doenças , Humanos , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nasofaringe/microbiologia , Fagocitose , Pneumonia Pneumocócica/epidemiologia , Risco , Emissões de Veículos
14.
Glia ; 67(7): 1254-1276, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30680794

RESUMO

Type I interferons (IFN-I) are the principal antiviral molecules of the innate immune system and can be made by most cell types, including central nervous system cells. IFN-I has been implicated in neuroinflammation during neurodegeneration, but its mechanism of induction and its consequences remain unclear. In the current study, we assessed expression of IFN-I in murine prion disease (ME7) and examined the contribution of the IFN-I receptor IFNAR1 to disease progression. The data indicate a robust IFNß response, specifically in microglia, with evidence of IFN-dependent genes in both microglia and astrocytes. This IFN-I response was absent in stimulator of interferon genes (STING-/- ) mice. Microglia showed increased numbers and activated morphology independent of genotype, but transcriptional signatures indicated an IFNAR1-dependent neuroinflammatory phenotype. Isolation of microglia and astrocytes demonstrated disease-associated microglial induction of Tnfα, Tgfb1, and of phagolysosomal system transcripts including those for cathepsins, Cd68, C1qa, C3, and Trem2, which were diminished in IFNAR1 and STING deficient mice. Microglial increases in activated cathepsin D, and CD68 were significantly reduced in IFNAR1-/- mice, particularly in white matter, and increases in COX-1 expression, and prostaglandin synthesis were significantly mitigated. Disease progressed more slowly in IFNAR1-/- mice, with diminished synaptic and neuronal loss and delayed onset of neurological signs and death but without effect on proteinase K-resistant PrP levels. Therefore, STING-dependent IFN-I influences microglial phenotype and influences neurodegenerative progression despite occurring secondary to initial degenerative changes. These data expand our mechanistic understanding of IFN-I induction and its impact on microglial function during chronic neurodegeneration.


Assuntos
Progressão da Doença , Interferon Tipo I/biossíntese , Proteínas de Membrana/deficiência , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Receptor de Interferon alfa e beta/deficiência , Animais , Doença Crônica , Feminino , Interferon Tipo I/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Fenótipo , Receptor de Interferon alfa e beta/genética
15.
Eur J Immunol ; 48(4): 705-715, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29349774

RESUMO

The effectiveness of many vaccines licensed for clinical use relates to the induction of neutralising antibodies, facilitated by the inclusion of vaccine adjuvants, particularly alum. However, the ability of alum to preferentially promote humoral rather than cellular, particularly Th1-type responses, is not well understood. We demonstrate that alum activates immunosuppressive mechanisms following vaccination, which limit its capacity to induce Th1 responses. One of the key cytokines limiting excessive immune responses is IL-10. Injection of alum primed draining lymph node cells for enhanced IL-10 secretion ex vivo. Moreover, at the site of injection, macrophages and dendritic cells were key sources of IL-10 expression. Alum strongly enhanced the transcription and secretion of IL-10 by macrophages and dendritic cells. The absence of IL-10 signalling did not compromise alum-induced cell infiltration into the site of injection, but resulted in enhanced antigen-specific Th1 responses after vaccination. In contrast to its decisive regulatory role in regulating Th1 responses, there was no significant change in antigen-specific IgG1 antibody production following vaccination with alum in IL-10-deficient mice. Overall, these findings indicate that injection of alum promotes IL-10, which can block Th1 responses and may explain the poor efficacy of alum as an adjuvant for inducing protective Th1 immunity.


Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , Células Dendríticas/imunologia , Interleucina-10/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células Th1/imunologia , Animais , Células Cultivadas , Escherichia coli/imunologia , Feminino , Interleucina-10/biossíntese , Interleucina-10/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vacinas/imunologia
16.
Nat Mater ; 22(3): 273-275, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36864156
17.
Mol Cell ; 44(2): 265-78, 2011 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-22017873

RESUMO

Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of proinflammatory cytokines, via a mechanism that remains undefined. Here we show that IL-1α is a substrate for granzyme B and that proteolysis potently enhanced the biological activity of this cytokine in vitro as well as in vivo. Consistent with this, compared with full-length IL-1α, granzyme B-processed IL-1α exhibited more potent activity as an immunoadjuvant in vivo. Furthermore, proteolysis of IL-1α within the same region, by proteases such as calpain and elastase, was also found to enhance its biological potency. Thus, IL-1α processing by multiple immune-related proteases, including granzyme B, acts as a switch to enhance the proinflammatory properties of this cytokine.


Assuntos
Granzimas/metabolismo , Interleucina-1alfa/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Células HeLa , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteólise
18.
Bioconjug Chem ; 29(3): 613-623, 2018 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-29300463

RESUMO

Mucosal immune responses are in the first line of defense against most infections and protective mucosal immunity can be achieved by mucosal vaccination. However, mucosal tolerance and physicochemical features of the mucosal environment pose challenging obstacles to the development of mucosal vaccines. Vaccine formulations must be designed to enhance stability at the mucosae and incorporate features that induce innate immunity at mucosal inductive sites. To face these challenges, a number of novel delivery systems for targeting of mucosal vaccines to specific mucosal locations have been developed. In addition, specific mucosal immune cell targeting can potentially be achieved with ligand-antigen bioconjugates, in particular, those directed to specific receptors expressed on Microfold (M) cells, mucosal epithelial cells, or mucosal antigen presenting cells (APCs). In this topical review, targeted strategies to enhance the effectiveness of mucosal vaccines are addressed, and obstacles to the design and progression of effective ligand-mediated mucosal vaccines are highlighted.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Mucosa/imunologia , Vacinação/métodos , Vacinas/administração & dosagem , Animais , Células Apresentadoras de Antígenos/imunologia , Células Epiteliais/imunologia , Humanos , Imunidade , Ligantes , Mucosa/citologia , Vacinas/química , Vacinas/imunologia
19.
Immunity ; 31(2): 331-41, 2009 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-19682929

RESUMO

Th17 cells, CD4(+) T cells that secrete interleukin-17 (IL-17), are pathogenic in autoimmune diseases and their development and expansion is driven by the cytokines IL-6, TGF-beta, IL-21, IL-1, and IL-23. However, there are also innate sources of IL-17. Here, we show that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta and IL-23, without T cell receptor engagement. IL-17-producing gammadelta T cells were found at high frequency in the brain of mice with experimental autoimmune encephalomyelitis (EAE). gammadelta T cells activated by IL-1beta and IL-23 promoted IL-17 production by CD4(+) T cells and increased susceptibility to EAE, suggesting that gammadelta T cells act in an amplification loop for IL-17 production by Th17 cells. Our findings demonstrate that gammadelta T cells activated by IL-1beta and IL-23 are an important source of innate IL-17 and IL-21 and provide an alternative mechanism whereby IL-1 and IL-23 may mediate autoimmune inflammation.


Assuntos
Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina-17/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoimunidade , Complexo CD3/imunologia , Complexo CD3/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-17/biossíntese , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Interleucina-23/imunologia , Interleucina-23/metabolismo , Interleucina-23/farmacologia , Interleucinas/imunologia , Interleucinas/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Interleucina/imunologia , Receptores de Interleucina/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-17/imunologia , Receptores do Ácido Retinoico/imunologia , Receptores do Ácido Retinoico/metabolismo , Receptores dos Hormônios Tireóideos/imunologia , Receptores dos Hormônios Tireóideos/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Interleucina 22
20.
Immunity ; 31(1): 84-98, 2009 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-19559631

RESUMO

Interleukin-33 (IL-33) is a member of the IL-1 family and is involved in polarization of T cells toward a T helper 2 (Th2) cell phenotype. IL-33 is thought to be activated via caspase-1-dependent proteolysis, similar to the proinflammatory cytokines IL-1 beta and IL-18, but this remains unproven. Here we showed that IL-33 was processed by caspases activated during apoptosis (caspase-3 and -7) but was not a physiological substrate for caspases associated with inflammation (caspase-1, -4, and -5). Furthermore, caspase-dependent processing of IL-33 was not required for ST2 receptor binding or ST2-dependent activation of the NF-kappaB transcription factor. Indeed, caspase-dependent proteolysis of IL-33 dramatically attenuated IL-33 bioactivity in vitro and in vivo. These data suggest that IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. Thus, caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL-33.


Assuntos
Caspase 1/imunologia , Caspase 3/imunologia , Caspase 7/imunologia , Interleucinas/imunologia , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Animais , Apoptose/imunologia , Caspase 1/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/genética , Interleucinas/metabolismo , Linfócitos/enzimologia , Linfócitos/imunologia , Linfócitos/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , NF-kappa B/metabolismo , Receptores de Interleucina
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