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1.
Nat Med ; 26(3): 430-440, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066977

RESUMO

Adjuvants are central to the efficacy of subunit vaccines. Aluminum hydroxide (alum) is the most commonly used vaccine adjuvant, yet its adjuvanticity is often weak and mechanisms of triggering antibody responses remain poorly understood. We demonstrate that site-specific modification of immunogens with short peptides composed of repeating phosphoserine (pSer) residues enhances binding to alum and prolongs immunogen bioavailability. The pSer-modified immunogens formulated in alum elicited greatly increased germinal center, antibody, neutralizing antibody, memory and long-lived plasma cell responses compared to conventional alum-adsorbed immunogens. Mechanistically, pSer-immunogen:alum complexes form nanoparticles that traffic to lymph nodes and trigger B cell activation through multivalent and oriented antigen display. Direct uptake of antigen-decorated alum particles by B cells upregulated antigen processing and presentation pathways, further enhancing B cell activation. These data provide insights into mechanisms of action of alum and introduce a readily translatable approach to significantly improve humoral immunity to subunit vaccines using a clinical adjuvant.


Assuntos
Adjuvantes Imunológicos/farmacologia , Hidróxido de Alumínio/farmacologia , Imunidade Humoral/efeitos dos fármacos , Peptídeos/imunologia , Engenharia de Proteínas , Animais , Apresentação do Antígeno/efeitos dos fármacos , Antígenos/metabolismo , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Endocitose/efeitos dos fármacos , Epitopos/imunologia , Imunização , Memória Imunológica/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , Peptídeos/química , Fosfosserina/metabolismo
2.
PLoS One ; 15(2): e0229461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32097435

RESUMO

T cells play an important role in controlling viral replication during HIV infection. An effective vaccine should, therefore, lead to the induction of a strong and early viral-specific CD8+ T cell response. While polyfunctional T cell responses are thought to be important contributors to the antiviral response, there is evidence to show that polyfunctional HIV- specific CD8+ T cells are just a small fraction of the total HIV-specific CD8+ T cells and may be absent in many individuals who control HIV replication, suggesting that other HIV-1 specific CD8+ effector T cell subsets may be key players in HIV control. Stem cell-like memory T cells (TSCM) are a subset of T cells with a long half-life and self-renewal capacity. They serve as key reservoirs for HIV and contribute a significant barrier to HIV eradication. The present study evaluated vaccine-induced antiviral responses and TSCM cells in volunteers vaccinated with a subtype C prophylactic HIV-1 vaccine candidate administered in a prime-boost regimen. We found that ADVAX DNA prime followed by MVA boost induced significantly more peripheral CD8+ TSCM cells and higher levels of CD8+ T cell-mediated inhibition of replication of different HIV-1 clades as compared to MVA alone and placebo. These findings are novel and provide encouraging evidence to demonstrate the induction of TSCM and cytotoxic immune responses by a subtype C HIV-1 prophylactic vaccine administered using a prime-boost strategy.


Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Memória Imunológica/imunologia , Células-Tronco/imunologia , Subpopulações de Linfócitos T/imunologia , Replicação Viral/imunologia , Vacinas contra a AIDS/administração & dosagem , Antivirais/administração & dosagem , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , HIV-1/classificação , Humanos , Memória Imunológica/efeitos dos fármacos , Masculino , Células-Tronco/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Vacinação , Replicação Viral/efeitos dos fármacos , Voluntários
3.
J Immunol Res ; 2019: 3616120, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31565660

RESUMO

Immune cell therapy has emerged as a promising approach to treat malignancies that were up until recently only treated on a palliative basis. Chimeric antigen receptor- (CAR-) modified T lymphocytes (T cells) in particular have proven to be very effective for certain hematological malignancies. The production of CAR T cells usually involves viral transduction and ex vivo culture of T cells. The aim of this study was to explore the use of human platelet lysate (HPL) compared to two commonly used supplements, human AB serum (ABS) and fetal bovine serum (FBS), for modified T cell production. For studying transduction, activated T cells were transduced with lentivirus to deliver GFP transgenes with three different promoters. Transduction efficiency (percent GFP) was similar among the supplements, and a modest increase in the transgene product (mean fluorescence intensity) was observed when HPL was used as a supplement compared to ABS. To study the effect of supplements on expansion, peripheral blood mononuclear cells (PBMCs) were activated and expanded in the presence of interleukin 2 (IL2) for fourteen days. T cell expansions using HPL and ABS were comparable and slightly less than the expansion obtained with FBS. Interestingly, cells expanded in media supplemented with HPL showed a higher percentage of T cells with a central memory phenotype compared to those expanded in ABS or FBS. Protein profiling revealed that the phenotypic differences may be explained by elevated levels of several cytokines in HPL, including IL7. The results suggest that the use of HPL as a cell culture supplement during the production of modified T cells is a reasonable alternative to ABS. Furthermore, the use of HPL may enhance in vivo performance of the final product by enriching for central memory T cells that are associated with long-term persistence following adoptive transfer.


Assuntos
Plaquetas/metabolismo , Meios de Cultivo Condicionados/farmacologia , Memória Imunológica/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Técnicas de Cultura de Células , Biologia Computacional/métodos , Citocinas/metabolismo , Expressão Gênica , Ontologia Genética , Genes Reporter , Vetores Genéticos/genética , Humanos , Lentivirus/genética , Proteoma , Proteômica , Linfócitos T/metabolismo , Transdução Genética , Transgenes
4.
Mol Cell ; 76(1): 110-125.e9, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31474573

RESUMO

Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.


Assuntos
Autofagia/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Senescência Celular/efeitos dos fármacos , Imunossenescência/efeitos dos fármacos , Fatores de Iniciação de Peptídeos/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Espermidina/farmacologia , Imunidade Adaptativa/efeitos dos fármacos , Fatores Etários , Envelhecimento , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/deficiência , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Células HEK293 , Humanos , Memória Imunológica/efeitos dos fármacos , Células Jurkat , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células NIH 3T3 , Fatores de Iniciação de Peptídeos/genética , Proteínas de Ligação a RNA/genética , Transdução de Sinais
5.
Nat Commun ; 10(1): 3666, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413301

RESUMO

Generating effective and durable T cell immunity is a critical prerequisite for vaccination against dengue virus (DENV) and other viral diseases. However, understanding the molecular mechanisms of vaccine-elicited T cell immunity remains a critical knowledge gap in vaccinology. In this study, we utilize single-cell RNA sequencing (scRNAseq) and longitudinal TCR clonotype analysis to identify a unique transcriptional signature present in acutely activated and clonally-expanded T cells that become committed to the memory repertoire. This effector/memory-associated transcriptional signature is dominated by a robust metabolic transcriptional program. Based on this transcriptional signature, we are able to define a set of markers that identify the most durable vaccine-reactive memory-precursor CD8+ T cells. This study illustrates the power of scRNAseq as an analytical tool to assess the molecular mechanisms of host control and vaccine modality in determining the magnitude, diversity and persistence of vaccine-elicited cell-mediated immunity.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Vacinas contra Dengue/farmacologia , Imunidade Celular/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Perfilação da Expressão Gênica , Humanos , Imunidade Celular/genética , Imunidade Celular/imunologia , Imunogenicidade da Vacina/genética , Imunogenicidade da Vacina/imunologia , Memória Imunológica/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência de RNA , Análise de Célula Única , Vacinas Atenuadas
6.
Infect Immun ; 87(10)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31358568

RESUMO

Development of long-term memory is crucial for vaccine-induced adaptive immunity against infectious diseases such as Staphylococcus aureus infection. Toxic shock syndrome toxin 1 (TSST-1), one of the superantigens produced by S. aureus, is a possible vaccine candidate against infectious diseases caused by this pathogen. We previously reported that vaccination with less toxic mutant TSST-1 (mTSST-1) induced T helper 17 (Th17) cells and elicited interleukin-17A (IL-17A)-mediated protection against S. aureus infection 1 week after vaccination. In the present study, we investigated the host immune response induced by mTSST-1 vaccination in the memory phase, 12 weeks after the final vaccination. The protective effect and IL-17A production after vaccination with mTSST-1 were eliminated because of IL-10 production. In the presence of IL-10-neutralizing monoclonal antibody (mAb), IL-17A production was restored in culture supernatants of CD4+ T cells and macrophages sorted from the spleens of vaccinated mice. Vaccinated mice treated with anti-IL-10 mAb were protected against systemic S. aureus infection in the memory phase. From these results, it was suggested that IL-10 produced in the memory phase suppresses the IL-17A-dependent vaccine effect through downregulation of IL-17A production.


Assuntos
Toxinas Bacterianas/genética , Enterotoxinas/genética , Interleucina-10/genética , Interleucina-17/genética , Infecções Estafilocócicas/prevenção & controle , Vacinas Antiestafilocócicas/genética , Staphylococcus aureus/efeitos dos fármacos , Superantígenos/genética , Células Th17/efeitos dos fármacos , Animais , Anticorpos Neutralizantes/farmacologia , Toxinas Bacterianas/administração & dosagem , Toxinas Bacterianas/biossíntese , Clonagem Molecular , Enterotoxinas/administração & dosagem , Enterotoxinas/biossíntese , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Memória Imunológica/efeitos dos fármacos , Interleucina-10/antagonistas & inibidores , Interleucina-10/imunologia , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Vacinas Antiestafilocócicas/administração & dosagem , Vacinas Antiestafilocócicas/biossíntese , Staphylococcus aureus/imunologia , Staphylococcus aureus/patogenicidade , Superantígenos/administração & dosagem , Superantígenos/biossíntese , Células Th17/imunologia , Vacinação , Vacinas Sintéticas
7.
J Immunol ; 203(2): 441-452, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31182479

RESUMO

Protease-activated receptor 2 (PAR-2) is expressed in various tissues, including lung, and when activated, promotes inflammation, differentiation, and migration of dendritic cells. We found that combining influenza virosomes containing hemagglutinin and neuraminidase with a PAR-2 agonist peptide (PAR-2AP) in an intranasal prime boost approach increased survival of mice challenged weeks later with lethal influenza virus over that by virosome or PAR-2AP prime boost alone. No weight loss occurred from influenza challenge after virosome-plus-PAR-2AP prime boost compared with either virosomes or PAR-2AP alone. Thus, virosomes plus PAR-2AP prevented morbidity as well as mortality. Through adoptive transfer, CD8+ lung T cells but not CD4+ T cells from virosomes plus PAR-2AP-primed mice protected from lethal influenza virus challenge and enhanced survival with less weight loss and faster recovery. Virosome-plus-PAR-2AP prime boost resulted in greater percentages of T effector memory phenotype cells (Tem) in lung, and higher frequencies of CD8 Tem and T central memory cells displayed effector functions in response to virus challenge in vivo. Virosome-plus-PAR-2AP prime boost also resulted in greater percentages of Ag-specific CD8+ T cells, both Tem and T central memory cells, in lungs of animals subsequently challenged with live influenza virus. Our findings indicate that PAR-2AP, a short peptide, may be a new and useful mucosal adjuvant.


Assuntos
Adjuvantes Imunológicos/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Receptor PAR-2/agonistas , Virossomos/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Cães , Feminino , Memória Imunológica/efeitos dos fármacos , Pulmão/imunologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/imunologia , Virossomos/efeitos dos fármacos
8.
Artigo em Inglês | MEDLINE | ID: mdl-31212664

RESUMO

Paraquat (PQ) is a toxic non-selective herbicide. To date, the effect of PQ on memory immune response is still unknown. We investigated the impact of PQ on memory immune response. Adult C57BL/6 mice were subcutaneously injected with 2 mg/kg PQ, 20 mg/kg PQ or vehicle control every three days for two weeks. A single injection of keyhole limpet hemocyanin (KLH) at day four after the initial PQ treatment was used to induce a primary immune response; a second KLH challenge was performed at three months post the first KLH immunization to induce a secondary immune response. In steady state, treatment with 20 mg/kg PQ reduced the level of serum total IgG, but not that of IgM; treatment with 20 mg/kg PQ decreased the number of effector and memory lymphocytes, but not naïve or inactivated lymphocytes. During the primary immune response to KLH, treatment with 20 mg/kg PQ did not influence the proliferation of lymphocytes or expression of co-stimulatory molecules. Instead, treatment with 20 mg/kg PQ increased the apoptosis of lymphocytes at late stage, but not early stage of the primary immune response. During the secondary immune response to KLH, treatment with 20 mg/kg PQ reduced the serum anti-KLH IgG and KLH-responsive CD4 T cells and B cells. Moreover, effector or activated lymphocytes were more sensitive to PQ-induced apoptosis in vitro. Treatment with 2 mg/kg PQ did not impact memory immune response to KLH. Thus, treatment with 20 mg/kg PQ increased apoptosis of late stage effector cells to yield less memory cells and thereafter impair memory immune response, providing a novel understanding of the immunotoxicity of PQ.


Assuntos
Adjuvantes Imunológicos/farmacologia , Apoptose/fisiologia , Hemocianinas/farmacologia , Herbicidas/farmacologia , Memória Imunológica/efeitos dos fármacos , Paraquat/farmacologia , Imunidade Adaptativa , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL
9.
PLoS Pathog ; 15(5): e1007811, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31107928

RESUMO

Leptospira interrogans are pathogenic spirochetes responsible for leptospirosis, a worldwide reemerging zoonosis. Many Leptospira serovars have been described, and prophylaxis using inactivated bacteria provides only short-term serovar-specific protection. Therefore, alternative approaches to limit severe leptospirosis in humans and morbidity in cattle would be welcome. Innate immune cells, including macrophages, play a key role in fighting infection and pathogen clearance. Recently, it has been shown that functional reprograming of innate immune cells through the activation of pattern recognition receptors leads to enhanced nonspecific antimicrobial responses upon a subsequent microbial encounter. This mechanism is known as trained immunity or innate immune memory. We have previously shown that oral treatment with Lactobacillus plantarum confers a beneficial effect against acute leptospirosis. Here, using a macrophage depletion protocol and live imaging in mice, we established the role of peritoneal macrophages in limiting the initial dissemination of leptospires. We further showed that intraperitoneal priming of mice with CL429, a TLR2 and NOD2 agonist known to mimic the modulatory effect of Lactobacillus, alleviated acute leptospiral infection. The CL429 treatment was characterized as a training effect since i.) it was linked to peritoneal macrophages that produced ex vivo more pro-inflammatory cytokines and chemokines against 3 different pathogenic serovars of Leptospira, independently of the presence of B and T cells, ii.) it had systemic effects on splenic cells and bone marrow derived macrophages, and iii.) it was sustained for 3 months. Importantly, trained macrophages produced more nitric oxide, a potent antimicrobial compound, which has not been previously linked to trained immunity. Accordingly, trained macrophages better restrict leptospiral survival. Finally, we could use CL429 to train ex vivo human monocytes that produced more cytokines upon leptospiral stimulation. In conclusion, host-directed treatment using a TLR2/NOD2 agonist could be envisioned as a novel prophylactic strategy against acute leptospirosis.


Assuntos
Memória Imunológica/imunologia , Leptospira interrogans/imunologia , Leptospirose/prevenção & controle , Macrófagos Peritoneais/imunologia , Proteína Adaptadora de Sinalização NOD2/agonistas , Bibliotecas de Moléculas Pequenas/farmacologia , Receptor 2 Toll-Like/agonistas , Animais , Células Cultivadas , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Leptospirose/imunologia , Leptospirose/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
10.
Arch Pharm Res ; 42(9): 754-765, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31049823

RESUMO

Allergic patients have life-long chronic inflammatory diseases with repeated relapses and exacerbations. Currently used allergy therapeutics have some limitations, which warrants a search for novel drug targets for allergy treatment. The studies on conventional allergic disease therapeutics have been focused on the pathology of allergy involving effector type 2 helper T cells (Th2). However, it has been suggested that allergen-specific memory Th2 cells are developed after the initial allergen exposure, which may play a critical role in the allergic relapses. Here, we discuss the contribution of memory Th2 cells to allergic diseases and the microenvironmental factors for chronic allergic disease persistence. Since most allergy drugs are prescribed to suppress symptoms of the diseases, targeting the different types of cells or factors contributing to allergic diseases persistence may cure the disease.


Assuntos
Antialérgicos/farmacologia , Homeostase/efeitos dos fármacos , Hipersensibilidade/tratamento farmacológico , Memória Imunológica/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Animais , Antialérgicos/química , Humanos , Hipersensibilidade/imunologia , Memória Imunológica/imunologia
11.
Front Immunol ; 10: 42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740103

RESUMO

The general understanding has been that only adaptive immunity is capable of immunological memory, but this concept has been challenged in recent years by studies showing that innate immune systems can mount resistance to reinfection-as the innate immune system can adapt its function following an insult. Innate immune training offers an attractive approach in intensive fish larval rearing, especially since the adaptive immune system is not fully developed. Trained innate immunity will potentially favor robust fish in terms of resistance to viral and bacterial diseases. So-called immunostimulants such as ß-glucans have for decades been used both in laboratories and in intensive fish aquaculture. Treatment of fish by ß-glucans (and by other substances with pathogen-associated molecular patterns) often induces activation of non-specific/innate immune mechanisms and induces higher disease resistance. The reported effects of e.g., ß-glucans fit nicely into the concept "trained innate immunity," but the research on fish does not yet include analysis of epigenetic changes that may be a prerequisite for long-lasting trained innate immunity. In this "perspective," we will discuss how in practical terms and based on prior knowledge one can introduce innate immune training in brood stock fish, and their offspring, and whether innate immune training by ß-glucans is a viable approach in larval aquaculture.


Assuntos
Adjuvantes Imunológicos/farmacologia , Aquicultura/métodos , Peixes/imunologia , Imunidade Inata/efeitos dos fármacos , Larva/efeitos dos fármacos , beta-Glucanas/farmacologia , Animais , Resistência à Doença/imunologia , Doenças dos Peixes/imunologia , Sistema Imunitário/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos
12.
Cancer Cell ; 35(2): 238-255.e6, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30753825

RESUMO

Cancer immunotherapies provide survival benefits in responding patients, but many patients fail to respond. Identifying the biology of treatment response and resistance are a priority to optimize drug selection and improve patient outcomes. We performed transcriptomic and immune profiling on 158 tumor biopsies from melanoma patients treated with anti-PD-1 monotherapy (n = 63) or combined anti-PD-1 and anti-CTLA-4 (n = 57). These data identified activated T cell signatures and T cell populations in responders to both treatments. Further mass cytometry analysis identified an EOMES+CD69+CD45RO+ effector memory T cell phenotype that was significantly more abundant in responders to combined immunotherapy compared with non-responders (n = 18). The gene expression profile of this population was associated with longer progression-free survival in patients treated with single agent and greater tumor shrinkage in both treatments.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Ipilimumab/administração & dosagem , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma/tratamento farmacológico , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Idoso , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígeno CTLA-4/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Lectinas Tipo C/imunologia , Antígenos Comuns de Leucócito/imunologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
13.
J Virol ; 93(9)2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30787150

RESUMO

Among the numerous immunological abnormalities observed in chronically human immunodeficiency virus (HIV)-infected individuals, perturbations in memory CD4 T cells are thought to contribute specifically to disease pathogenesis. Among these, functional imbalances in the frequencies of T regulatory cells (Tregs) and interleukin 17 (IL-17)/IL-22-producing Th cells (Th17/Th22) from mucosal sites and T follicular helper (Tfh) cells in lymph nodes are thought to facilitate specific aspects of disease pathogenesis. However, while preferential infection of Tfh cells is widely thought to create an important viral reservoir in an immunologically privileged site in vivo, whether immunological perturbations among memory CD4 T cell populations are attributable to their relative infectivity by the virus in vivo is unclear. Here we studied peripheral blood and lymphoid tissues from antiretroviral (ARV)-treated and ARV-naive Asian macaques and isolated functionally defined populations of memory CD4 T cells. We then assessed the degree to which these populations were infected by simian immunodeficiency virus (SIV) in vivo, to determine whether particular functionally identified populations of memory CD4 T cells were preferentially infected by the virus. We found that SIV did not preferentially infect Th17 cells, compared to Th1 cells, Th2 cells, or Tregs. Moreover, Th17 cells contributed proportionately to the total pool of infected cells. Taken together, our data suggest that, although Tfh cells are more prone to harbor viral DNA, other functionally polarized cells are equally infected by the virus in vivo and Th17 cells are not preferentially infected.IMPORTANCE Functional perturbations of memory CD4 T cells have been suggested to underlie important aspects of HIV disease progression. However, the mechanisms underlying these perturbations remain unclear. Using a nonhuman primate model of HIV, we show that SIV infects functionally defined populations of memory CD4 T cells equally in different anatomic sites. Thus, preferential infection by the virus is unlikely to cause functional perturbations.


Assuntos
DNA Viral/imunologia , Memória Imunológica/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antirretrovirais/farmacologia , Macaca mulatta , Macaca nemestrina , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Linfócitos T Auxiliares-Indutores/virologia
14.
Sci Transl Med ; 11(480)2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787167

RESUMO

The incidence of allergic diseases has increased over the past 50 years, likely due to environmental factors. However, the nature of these factors and the mode of action by which they induce the type 2 immune deviation characteristic of atopic diseases remain unclear. It has previously been reported that dietary sodium chloride promotes the polarization of T helper 17 (TH17) cells with implications for autoimmune diseases such as multiple sclerosis. Here, we demonstrate that sodium chloride also potently promotes TH2 cell responses on multiple regulatory levels. Sodium chloride enhanced interleukin-4 (IL-4) and IL-13 production while suppressing interferon-γ (IFN-γ) production in memory T cells. It diverted alternative T cell fates into the TH2 cell phenotype and also induced de novo TH2 cell polarization from naïve T cell precursors. Mechanistically, sodium chloride exerted its effects via the osmosensitive transcription factor NFAT5 and the kinase SGK-1, which regulated TH2 signature cytokines and master transcription factors in hyperosmolar salt conditions. The skin of patients suffering from atopic dermatitis contained elevated sodium compared to nonlesional atopic and healthy skin. These results suggest that sodium chloride represents a so far overlooked cutaneous microenvironmental checkpoint in atopic dermatitis that can induce TH2 cell responses, the orchestrators of atopic diseases.


Assuntos
Microambiente Celular , Pele/citologia , Cloreto de Sódio/farmacologia , Células Th2/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Citocinas/metabolismo , Dermatite Atópica/patologia , Células HEK293 , Humanos , Memória Imunológica/efeitos dos fármacos , Íons , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Sódio/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
15.
J Immunol ; 202(4): 1088-1098, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626691

RESUMO

Although the methylation status of histone H3K27 plays a critical role in CD4+ T cell differentiation and its function, the role of Utx histone H3K27 demethylase in the CD8+ T cell-dependent immune response remains unclear. We therefore generated T cell-specific Utx flox/flox Cd4-Cre Tg (Utx KO) mice to determine the role of Utx in CD8+ T cells. Wild-type (WT) and Utx KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8+ T cells. There was no significant difference in the number of Ag-specific CD8+ T cells upon primary infection between WT and Utx KO mice. However, Utx deficiency resulted in more Ag-specific CD8+ T cells upon secondary infection. Adoptive transfer of Utx KO CD8+ T cells resulted in a larger number of memory cells in the primary response than in WT. We observed a decreased gene expression of effector-associated transcription factors, including Prdm1 encoding Blimp1, in Utx KO CD8+ T cells. We confirmed that the trimethylation level of histone H3K27 in the Prdm1 gene loci in the Utx KO cells was higher than in the WT cells. The treatment of CD8+ T cells with Utx-cofactor α-ketoglutarate hampered the memory formation, whereas Utx inhibitor GSK-J4 enhanced the memory formation in WT CD8+ T cells. These data suggest that Utx negatively controls the memory formation of Ag-stimulated CD8+ T cells by epigenetically regulating the gene expression. Based on these findings, we identified a critical link between Utx and the differentiation of Ag-stimulated CD8+ T cells.


Assuntos
Antígenos CD8/imunologia , Histonas/imunologia , Memória Imunológica/imunologia , Histona Desmetilases com o Domínio Jumonji/imunologia , Animais , Benzazepinas/farmacologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Histonas/metabolismo , Memória Imunológica/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pirimidinas/farmacologia
16.
Trends Immunol ; 40(1): 66-80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30595189

RESUMO

Infiltrating and tissue-resident myeloid cells are essential regulators of innate and adaptive immunity. During inflammation, and in response to microbial products, these cells can adapt to microenvironmental conditions and acquire specialized functions, including phagocytosis and the production of proinflammatory cytokines. Such myeloid plasticity is driven, in part, by epigenetic dynamics that can sustain stable phenotypes after activation, and which may lead to maladaptive cell polarization states associated with inflammation and autoimmunity. Here, we review recent reports describing epigenetic mechanisms linked to such polarization states and innate immune memory (tolerance and training) in monocyte and macrophage lineages. We discuss how these mechanisms might be targeted to develop putative immunomodulatory tools that might be used to treat a variety of immune-mediated diseases.


Assuntos
Epigênese Genética/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Células Mieloides/efeitos dos fármacos , Animais , Epigênese Genética/genética , Epigênese Genética/imunologia , Humanos , Imunidade Inata/imunologia , Fatores Imunológicos/imunologia , Memória Imunológica/imunologia , Células Mieloides/imunologia
17.
Scand J Rheumatol ; 48(3): 225-229, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30516404

RESUMO

OBJECTIVE: Dermatomyositis (DM) is an idiopathic inflammatory myopathy which often involves the lungs. DM is likely to be associated with aberrant T- and B-cell activation in the pathogenesis because of the proven effectiveness of T- and B-cell-targeted treatments. Assuming that the aberrant activation is reflected by biases in the lymphocyte subset repertoires, we aimed to elucidate these biases, especially in relation to clinical features of DM. METHOD: Based on the immunophenotyping standardized by the Human Immunology Project Consortium, untreated 13 DM patients, including seven patients with interstitial lung disease (ILD), and 18 age-matched healthy donors (HDs) were examined for proportions of peripheral blood lymphocyte subsets. Six DM patients were examined before and after successful induction of remission. RESULTS: Naïve CD4+ T cells and naïve B cells were more abundant, while there were fewer naïve CD8+ T cells, central memory CD8+ T cells, effector memory CD4+ T cells, Th1 cells, Tfh cells, and memory B cells in DM patients than in HDs. When the patients were subgrouped according to the presence of ILD, the lymphocyte subset repertoires in the patients with ILD contributed to the statistical differences in all the biased lymphocyte subset proportions. After treatment, transitional B cells vanished and there was an increase in memory B cells. CONCLUSION: The lymphocyte subset repertoires in the DM patients were biased, and were associated with the presence of ILD and disease activity of DM.


Assuntos
Dermatomiosite , Imunossupressores , Doenças Pulmonares Intersticiais , Subpopulações de Linfócitos/imunologia , Dermatomiosite/complicações , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Feminino , Humanos , Memória Imunológica/efeitos dos fármacos , Imunofenotipagem/métodos , Imunofenotipagem/estatística & dados numéricos , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Japão , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente
18.
Front Immunol ; 9: 2775, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30542351

RESUMO

The chemokine receptor XCR1 is known to be selectively expressed by cross-presenting dendritic cells (DCs), while its ligand XCL1/lymphotactin is mainly produced by activated CD8+ T cells and natural killer cells. Recent studies have shown that XCL1-antigen fusion proteins efficiently induce CD8+ T cell responses by preferentially delivering antigens to XCR1+ DCs. However, XCL1 per se was found to be a poor adjuvant for induction of CD8+ T cell responses. XCL1 is unique because of its lack of one of the two disulfide bonds commonly conserved in all other chemokines and thus has an unstable structure with a relatively weak chemokine activity. In the present study, we generated a variant form of murine XCL1 termed mXCL1-V21C/A59C that contained a second disulfide bond to stabilize its chemokine structure. We confirmed that mXCL1-V21C/A59C had much more potent chemotactic and calcium mobilization activities than the wild type XCL1 (mXCL1-WT). Intradermal injection of mXCL1-V21C/A59C, but not that of mXCL1-WT, significantly increased the accumulation of XCR1+CD103+ DCs in the injection site, and most of the accumulated XCR1+CD103+ DCs were found to take up co-injected ovalbumin (OVA). Furthermore, recruited XCR1+CD103+ DCs efficiently migrated to the draining lymph nodes and stayed for a prolonged period of time. Consequently, mXCL1-V21C/A59C strongly induced OVA-specific CD8+ T cells. The combination of OVA and mXCL1-V21C/A59C well protected mice from E.G7-OVA tumor growth in both prophylactic and therapeutic protocols. Finally, memory CTL responses were efficiently induced in mice immunized with OVA and mXCL1-V21C/A59C. Although intradermal injection of OVA and polyinosinic-polycytidylic acid (poly(I:C)) as an adjuvant also induced CD8+ T cell responses to OVA, poly (I:C) poorly recruited XCR1+CD103+ DCs in the injection site and failed to induce significant memory CTL responses to OVA. Collectively, our findings demonstrate that a highly active form of XCL1 is a promising vaccine adjuvant for cross-presenting DCs to induce antigen-specific effector and memory CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocinas C/imunologia , Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Memória Imunológica/imunologia , Linfocinas/imunologia , Sialoglicoproteínas/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Antígenos/imunologia , Antígenos CD/imunologia , Cálcio/imunologia , Linhagem Celular , Apresentação Cruzada/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Cadeias alfa de Integrinas/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/imunologia
19.
Ann Saudi Med ; 38(6): 413-419, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30531175

RESUMO

BACKGROUND: Globally, about 300 million people are infected with hepatitis B virus (HBV). Among the effective approaches to fight HBV infection is immunization. In 1989, an obligatory hepatitis B vaccine program was launched in Saudi Arabia. OBJECTIVE: Assess hepatitis B surface antibody (anti-HBs) levels among the medical students before and after receiving booster doses of HBV vaccine. DESIGN: Cross-sectional. SETTING: Taibah University. SUBJECTS AND METHODS: Students born between 1993 and 1995 were recruited in this study from the Occupational Health Clinic. Students were screened for anti-HBs levels using chemiluminescent microparticle immunoassay (CMIA) before and after booster HBV vaccine doses. MAIN OUTCOME MEASURES: Anti-HBs levels before and after booster doses. SAMPLE SIZE: 335. RESULTS: About half of participants (n=164, 49%) had protective anti-HBs levels ( greater than or equal 10 mIU/mL) to the original primary series of HBV vaccine and received no booster doses. The reimaining 171 (51%) participants were at risk of HBV infection since their anti-HBs levels were less than 10 mIU/mL, despite having received the original primary HBV vaccine. The levels of anti-HBs were higher in female than in male students (P less than .001). In addition, female students showed a stronger humoral immune response to the booster vaccine than male students (P less than .001). When participants were given the three boosters, most participants (98.3%) showed anti-HBs levels of greater than or equal 10 mIU/mL. The results also showed a strong correlation between pre-booster and post-booster anti-HBs levels in the greater than or equal 10 mIU/mL group (r2= 0.52, P less than .001) but not in less than 10 mIU/mL group (r2= 0.003, P=.53). CONCLUSION: A considerable portion of the participants (about 51%) were at risk of HBV infection since their anti-HBs levels were less than 10 mIU/mL. Booster doses significantly trigger memory immune response and this ensured their protection against the virus. Pre-booster anti-HBs level are a good predictive of post-booster anti-HBs levels in greater than or equal 10 mIU/mL group. LIMITATIONS: The sample size was small. Shortage of collaborators. CONFLICT OF INTEREST: None.


Assuntos
Anticorpos Anti-Hepatite B/análise , Antígenos de Superfície da Hepatite B/análise , Vacinas contra Hepatite B/administração & dosagem , Vírus da Hepatite B/imunologia , Hepatite B , Adulto , Relação Dose-Resposta a Droga , Feminino , Hepatite B/epidemiologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Humanos , Imunidade Humoral/imunologia , Imunização Secundária/métodos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Masculino , Medição de Risco , Arábia Saudita/epidemiologia , Fatores Sexuais , Estudantes de Medicina/estatística & dados numéricos
20.
Int J Nanomedicine ; 13: 6699-6715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425484

RESUMO

Background: Influenza (flu) is a constant threat to humans and animals, and vaccination is one of the most effective ways to mitigate the disease. Due to incomplete protection induced by current flu vaccines, development of novel flu vaccine candidates is warranted to achieve greater efficacy against constantly evolving flu viruses. Methods: In the present study, we used liposome nanoparticle (<200 nm diameter)-based subunit flu vaccine containing ten encapsulated highly conserved B and T cell epitope peptides to induce protective immune response against a zoonotic swine influenza A virus (SwIAV) H1N1 challenge infection in a pig model. Furthermore, we used monosodium urate (MSU) crystals as an adjuvant and co-administered the vaccine formulation as an intranasal mist to flu-free nursery pigs, twice at 3-week intervals. Results: Liposome peptides flu vaccine delivered with MSU adjuvant improved the hemagglutination inhibition antibody titer and mucosal IgA response against the SwIAV challenge and also against two other highly genetically variant IAVs. Liposomal vaccines also enhanced the frequency of peptides and virus-specific T-helper/memory cells and IFN-γ response. The improved specific cellular and mucosal humoral immune responses in adjuvanted liposomal peptides flu vaccine partially protected pigs from flu-induced fever and pneumonic lesions, and reduced the nasal virus shedding and viral load in the lungs. Conclusion: Overall, our study shows great promise for using liposome and MSU adjuvant- based subunit flu vaccine through the intranasal route, and provides scope for future, pre-clinical investigations in a pig model for developing potent human intranasal subunit flu vaccines.


Assuntos
Adjuvantes Imunológicos/farmacologia , Imunidade , Vacinas contra Influenza/imunologia , Nanopartículas/química , Infecções por Orthomyxoviridae/imunologia , Peptídeos/imunologia , Ácido Úrico/farmacologia , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Sequência de Aminoácidos , Animais , Formação de Anticorpos/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Citocinas/biossíntese , Cães , Imunidade/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1 , Lipossomos , Pulmão/patologia , Pulmão/virologia , Células Madin Darby de Rim Canino , Nanopartículas/ultraestrutura , Infecções por Orthomyxoviridae/virologia , Peptídeos/química , Sus scrofa , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Vacinação , Carga Viral/efeitos dos fármacos
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