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1.
Front Immunol ; 12: 726960, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671348

RESUMO

Objectives: In the context of the Covid-19 pandemic, the fast development of vaccines with efficacy of around 95% preventing Covid-19 illness provides a unique opportunity to reduce the mortality associated with the pandemic. However, in the absence of efficacious prophylactic medications and few treatments for this infection, the induction of a fast and robust protective immunity is required for effective disease control, not only to prevent the disease but also the infection and shedding/transmission. The objective of our study was to analyze the level of specific humoral and cellular T-cell responses against the spike protein of SARS-CoV-2 induced by two mRNA-based vaccines (BNT162b2 and mRNA-1273), but also how long it takes after vaccination to induce these protective humoral and cellular immune responses. Methods: We studied in 40 healthy (not previously infected) volunteers vaccinated with BNT162b2 or mRNA-1273 vaccines the presence of spike-specific IgG antibodies and SARS-CoV-2-specific T cells at 3, 7 and 14 days after receiving the second dose of the vaccine. The specific T-cell response was analyzed stimulating fresh whole blood from vaccinated volunteers with SARS-CoV-2 peptides and measuring the release of cytokines secreted by T cells in response to SARS-CoV-2 stimulation. Results: Our results indicate that the immunization capacity of both vaccines is comparable. However, although both BNT162b2 and mRNA-1273 vaccines can induce early B-cell and T-cell responses, these vaccine-mediated immune responses do not reach their maximum values until 14 days after completing the vaccination schedule. Conclusion: This refractory period in the induction of specific immunity observed after completing the vaccination could constitute a window of higher infection risk, which could explain some emerging cases of SARS-CoV-2 infection in vaccinated people.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , COVID-19/prevenção & controle , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Esquemas de Imunização , Imunoglobulina G/sangue , Contagem de Linfócitos , Masculino , Estudos Prospectivos , Vacinação
2.
Front Immunol ; 12: 727850, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34671350

RESUMO

Mass SARS-Cov-2 vaccination campaign represents the only strategy to defeat the global pandemic we are facing. Immunocompromised patients represent a vulnerable population at high risk of developing severe COVID-19 and thus should be prioritized in the vaccination programs and in the study of the vaccine efficacy. Nevertheless, most data on efficacy and safety of the available vaccines derive from trials conducted on healthy individuals; hence, studies on immunogenicity of SARS-CoV2 vaccines in such populations are deeply needed. Here, we perform an observational longitudinal study analyzing the humoral and cellular response following the BNT162b2 mRNA COVID-19 vaccine in a cohort of patients affected by inborn errors of immunity (IEI) compared to healthy controls (HC). We show that both IEI and HC groups experienced a significant increase in anti-SARS-CoV-2 Abs 1 week after the second scheduled dose as well as an overall statistically significant expansion of the Ag-specific CD4+CD40L+ T cells in both HC and IEI. Five IEI patients did not develop any specific CD4+CD40L+ T cellular response, with one of these patients unable to also mount any humoral response. These data raise immunologic concerns about using Ab response as a sole metric of protective immunity following vaccination for SARS-CoV-2. Taken together, these findings suggest that evaluation of vaccine-induced immunity in this subpopulation should also include quantification of Ag-specific T cells.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/imunologia , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina/imunologia , Doenças da Imunodeficiência Primária/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Contagem de Linfócito CD4 , COVID-19/prevenção & controle , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Hospedeiro Imunocomprometido/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Vacinação , Adulto Jovem
3.
Cell Rep ; 36(11): 109708, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34506741

RESUMO

Cellular immunity is important in determining the disease severity of COVID-19 patients. However, current understanding of SARS-CoV-2 epitopes mediating cellular immunity is limited. Here we apply T-Scan, a recently developed method, to identify CD8+ T cell epitopes from COVID-19 patients of four major HLA-A alleles. Several identified epitopes are conserved across human coronaviruses, which might mediate pre-existing cellular immunity to SARS-CoV-2. In addition, we identify and validate four epitopes that were mutated in the newly circulating variants, including the Delta variant. The mutations significantly reduce T cell responses to the epitope peptides in convalescent and vaccinated samples. We further determine the crystal structure of HLA-A∗02:01/HLA-A∗24:02 in complex with the epitope KIA_S/NYN_S, respectively, which reveals the importance of K417 and L452 of the spike protein for binding to HLA. Our data suggest that evading cellular immunity might contribute to the increased transmissibility and disease severity associated with the new SARS-CoV-2 variants.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/imunologia , Imunidade Celular/imunologia , SARS-CoV-2/imunologia , Sequência de Aminoácidos , Humanos , Glicoproteína da Espícula de Coronavírus/imunologia
5.
Int Immunol ; 33(10): 529-540, 2021 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-34491327

RESUMO

Coronavirus disease 2019 (COVID-19) has caused millions of deaths, and serious consequences to public health, economies and societies. Rapid responses in vaccine development have taken place since the isolation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the release of the viral genome sequence. By 21 May 2021, 101 vaccines were under clinical trials, and published data were available for 18 of them. Clinical study results from some vaccines indicated good immunogenicity and acceptable reactogenicity. Here, we focus on these 18 vaccines that had published clinical data to dissect the induced humoral and cellular immune responses as well as their safety profiles and protection efficacy.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Animais , Humanos , Imunogenicidade da Vacina/imunologia , SARS-CoV-2/imunologia
6.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34551974

RESUMO

Vaccination is an essential public health measure for infectious disease prevention. The exposure of the immune system to vaccine formulations with the appropriate kinetics is critical for inducing protective immunity. In this work, faceted microneedle arrays were designed and fabricated utilizing a three-dimensional (3D)-printing technique called continuous liquid interface production (CLIP). The faceted microneedle design resulted in increased surface area as compared with the smooth square pyramidal design, ultimately leading to enhanced surface coating of model vaccine components (ovalbumin and CpG). Utilizing fluorescent tags and live-animal imaging, we evaluated in vivo cargo retention and bioavailability in mice as a function of route of delivery. Compared with subcutaneous bolus injection of the soluble components, microneedle transdermal delivery not only resulted in enhanced cargo retention in the skin but also improved immune cell activation in the draining lymph nodes. Furthermore, the microneedle vaccine induced a potent humoral immune response, with higher total IgG (Immunoglobulin G) and a more balanced IgG1/IgG2a repertoire and achieved dose sparing. Furthermore, it elicited T cell responses as characterized by functional cytotoxic CD8+ T cells and CD4+ T cells secreting Th1 (T helper type 1)-cytokines. Taken together, CLIP 3D-printed microneedles coated with vaccine components provide a useful platform for a noninvasive, self-applicable vaccination.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Impressão Tridimensional/instrumentação , Vacinação/métodos , Vacinas/administração & dosagem , Administração Cutânea , Animais , Sistemas de Liberação de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia
7.
Expert Rev Vaccines ; 20(9): 1059-1063, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365880

RESUMO

INTRODUCTION: The Development of the SARS-CoV-2 virus vaccine and its update on an ongoing pandemic is the first subject of the world health agenda. AREAS COVERED: First, we will scrutinize the biological features of the measles virus (MV), variola virus (smallpox virus), influenza virus, and their vaccines to compare them with the SARS-CoV-2 virus and vaccine. Next, we will discuss the statistical details of measuring the effectiveness of an improved vaccine. EXPERT OPINION: Amidst the pandemic, we ought to acknowledge our prior experiences with respiratory viruses and vaccines. In the planning stage of observational Phase-III vaccine effectiveness studies, the sample size, sampling method, statistical model, and selection of variables are crucial in obtaining high-quality and valid results.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Celular/imunologia , SARS-CoV-2/imunologia , COVID-19/patologia , Humanos , Vacinas contra Influenza/imunologia , Vacinação em Massa/métodos , Vírus do Sarampo/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Orthomyxoviridae/imunologia , Vacina Antivariólica/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Vírus da Varíola/imunologia
8.
Ann Rheum Dis ; 80(10): 1322-1329, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34362747

RESUMO

OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.


Assuntos
Doenças Autoimunes/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Hospedeiro Imunocomprometido/imunologia , Imunogenicidade da Vacina/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Doenças Autoimunes/tratamento farmacológico , Feminino , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunossupressores/imunologia , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Linfócitos T/imunologia
9.
Eur J Immunol ; 51(10): 2478-2484, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34350584

RESUMO

Treatment with convalescent plasma has been shown to be safe in coronavirus disease in 2019 (COVID-19) infection, although efficacy reported in immunocompetent patients varies. Nevertheless, neutralizing antibodies are a key requisite in the fight against viral infections. Patients depleted of antibody-producing B cells, such as those treated with rituximab (anti-CD20) for hematological malignancies, lack a fundamental part of their adaptive immunity. Treatment with convalescent plasma appears to be of general benefit in this particularly vulnerable cohort. We analyzed clinical course and inflammation markers of three B-cell-depleted patients suffering from COVID-19 who were treated with convalescent plasma. In addition, we measured serum antibody levels as well as peripheral blood CD38/HLA-DR-positive T-cells ex vivo and CD137-positive T-cells after in vitro stimulation with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-derived peptides in these patients. We observed that therapy with convalescent plasma was effective in all three patients and analysis of CD137-positive T-cells after stimulation with SARS-CoV-2 peptides showed an increase in peptide-specific T-cells after application of convalescent plasma. In conclusion, we here demonstrate efficacy of convalescent plasma therapy in three B-cell-depleted patients and present data that suggest that while application of convalescent plasma elevates systemic antibody levels only transiently, it may also boost specific T-cell responses.


Assuntos
Anticorpos Antivirais/sangue , Linfócitos B/imunologia , COVID-19/terapia , Linfócitos T/imunologia , Adolescente , Idoso , Anticorpos Neutralizantes/sangue , Linfócitos B/citologia , Humanos , Imunidade Celular/imunologia , Imunização Passiva/métodos , Contagem de Linfócitos , Depleção Linfocítica , Linfoma de Células B/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Rituximab/efeitos adversos , SARS-CoV-2/imunologia , Resultado do Tratamento , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
10.
EBioMedicine ; 70: 103524, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34391096

RESUMO

BACKGROUND: Patients with chronic renal insufficiency on maintenance haemodialysis face an increased risk of COVID-19 induced mortality and impaired vaccine responses. To date, only a few studies have addressed SARS-CoV-2 vaccine elicited immunity in this immunocompromised population. METHODS: We assessed immunogenicity of the mRNA vaccine BNT162b2 in at-risk dialysis patients and characterised systemic cellular and humoral immune responses in serum and saliva using interferon γ release assay and multiplex-based cytokine and immunoglobulin measurements. We further compared binding capacity and neutralization efficacy of vaccination-induced immunoglobulins against emerging SARS-CoV-2 variants Alpha, Beta, Epsilon and Cluster 5 by ACE2-RBD competition assay. FINDINGS: Patients on maintenance haemodialysis exhibit detectable but variable cellular and humoral immune responses against SARS-CoV-2 and variants of concern after a two-dose regimen of BNT162b2. Although vaccination-induced immunoglobulins were detectable in saliva and plasma, both anti-SARS-CoV-2 IgG and neutralization efficacy was reduced compared to a vaccinated non-dialysed control population. Similarly, T-cell mediated interferon γ release after stimulation with SARS-CoV-2 spike peptides was significantly diminished. INTERPRETATION: Quantifiable humoral and cellular immune responses after BNT162b2 vaccination in individuals on maintenance haemodialysis are encouraging, but urge for longitudinal follow-up to assess longevity of immunity. Diminished virus neutralization and interferon γ responses in the face of emerging variants of concern may favour this at-risk population for re-vaccination using modified vaccines at the earliest opportunity. FUNDING: Initiative and Networking Fund of the Helmholtz Association of German Research Centres, EU Horizon 2020 research and innovation program, State Ministry of Baden-Württemberg for Economic Affairs, Labour and Tourism.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunogenicidade da Vacina/imunologia , SARS-CoV-2/imunologia , Vacinas Sintéticas/imunologia , Idoso , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Diálise Renal/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação/métodos
11.
Immunol Res ; 69(6): 576-583, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34417958

RESUMO

The development of vaccines to prevent SARS-CoV-2 infection has mainly relied on the induction of neutralizing antibodies (nAbs) to the Spike protein of SARS-CoV-2, but there is growing evidence that T cell immune response can contribute to protection as well. In this study, an anti-receptor binding domain (RBD) antibody assay and an INFγ-release assay (IGRA) were used to detect humoral and cellular responses to the Pfizer-BioNTech BNT162b2 vaccine in three separate cohorts of COVID-19-naïve patients: 108 healthcare workers (HCWs), 15 elderly people, and 5 autoimmune patients treated with immunosuppressive agents. After the second dose of vaccine, the mean values of anti-RBD antibodies (Abs) and INFγ were 123.33 U/mL (range 27.55-464) and 1513 mIU/mL (range 145-2500) in HCWs and 210.7 U/mL (range 3-500) and 1167 mIU/mL (range 83-2500) in elderly people. No correlations between age and immune status were observed. On the contrary, a weak but significant positive correlation was found between INFγ and anti-RBD Abs values (rho = 0.354, p = 0.003). As to the autoimmune cohort, anti-RBD Abs were not detected in the two patients with absent peripheral CD19+B cells, despite high INFγ levels being observed in all 5 patients after vaccination. Even though the clinical relevance of T cell response has not yet been established as a correlate of vaccine-induced protection, IGRA testing has showed optimal sensitivity and specificity to define vaccine responders, even in patients lacking a cognate antibody response to the vaccine.


Assuntos
Vacinas contra COVID-19/imunologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Hospedeiro Imunocomprometido/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Pessoal de Saúde/estatística & dados numéricos , Humanos , Imunogenicidade da Vacina/imunologia , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Interferon gama/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Domínios Proteicos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Adulto Jovem
12.
Nat Commun ; 12(1): 4984, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404803

RESUMO

SARS-CoV-2 vaccination has been launched worldwide to build effective population-level immunity to curb the spread of this virus. The effectiveness and duration of protective immunity is a critical factor for public health. Here, we report the kinetics of the SARS-CoV-2 specific immune response in 204 individuals up to 1-year after recovery from COVID-19. RBD-IgG and full-length spike-IgG concentrations and serum neutralizing capacity decreases during the first 6-months, but is maintained stably up to 1-year after hospital discharge. Even individuals who had generated high IgG levels during early convalescent stages had IgG levels that had decreased to a similar level one year later. Notably, the RBD-IgG level positively correlates with serum neutralizing capacity, suggesting the representative role of RBD-IgG in predicting serum protection. Moreover, viral-specific cellular immune protection, including spike and nucleoprotein specific, persisted between 6 months and 12 months. Altogether, our study supports the persistence of viral-specific protective immunity over 1 year.


Assuntos
COVID-19/imunologia , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , Humanos , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
13.
Biomolecules ; 11(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34439863

RESUMO

MicroRNAs (miRNAs) are members of the non-coding regulatory RNA family that play pivotal roles in physiological and pathological conditions, including immune response. They are particularly interesting as promising therapeutic targets, prognostic and diagnostic markers due to their easy detection in body fluids and stability. There is accumulating evidence that different miRNAs provide disease-specific signatures in liquid samples of distinct kidney injuries. Using experimental models and human samples, there have been numerous suggestions that immune-related miRNAs are also important contributors to the development of different kidney diseases as well as important markers for monitoring response after kidney transplantation. However, there are limited data for understanding their function in the molecular pathways of allograft pathologies. In our review, we focused on microRNAs that are related to different aspects of immune response after kidney transplantation.


Assuntos
Rejeição de Enxerto/imunologia , Imunidade Celular/imunologia , Transplante de Rim/efeitos adversos , MicroRNAs/imunologia , Complicações Pós-Operatórias/imunologia , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Humanos , Nefropatias/diagnóstico , Nefropatias/imunologia , Nefropatias/cirurgia , Transplante de Rim/tendências , MicroRNAs/genética , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/genética
14.
Sci Rep ; 11(1): 15963, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354188

RESUMO

One group of promising pest control agents are the entomopathogenic fungi; one such example is Conidiobolus coronatus, which produces a range of metabolites. Our present findings reveal for the first time that C. coronatus also produces dodecanol, a compound widely used to make surfactants and pharmaceuticals, and enhance flavors in food. The main aim of the study was to determine the influence of dodecanol on insect defense systems, i.e. cuticular lipid composition and the condition of insect immunocompetent cells; hence, its effect was examined in detail on two species differing in susceptibility to fungal infection: Galleria mellonella and Calliphora vicina. Dodecanol treatment elicited significant quantitative and qualitative differences in cuticular free fatty acid (FFA) profiles between the species, based on gas chromatography analysis with mass spectrometry (GC/MS), and had a negative effect on G. mellonella and C. vicina hemocytes and a Sf9 cell line in vitro: after 48 h, almost all the cells were completely disintegrated. The metabolite had a negative effect on the insect defense system, suggesting that it could play an important role during C. coronatus infection. Its high insecticidal activity and lack of toxicity towards vertebrates suggest it could be an effective insecticide.


Assuntos
Conidiobolus/metabolismo , Dodecanol/metabolismo , Dodecanol/farmacologia , Animais , Calliphoridae , Conidiobolus/química , Conidiobolus/patogenicidade , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Fungos/química , Fungos/metabolismo , Cromatografia Gasosa-Espectrometria de Massas/métodos , Hemócitos/metabolismo , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Insetos/metabolismo , Inseticidas , Larva/metabolismo , Mariposas/metabolismo
15.
Vet Microbiol ; 260: 109182, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315003

RESUMO

Immunosuppression can increase the susceptibility of chickens to other disease-causing pathogens and interfere with the efficacy of vaccination against those pathogens. Chicken anaemia virus (CAV) and infectious bursal disease virus (IBDV) are common causes of immunosuppression in chickens. Immunosuppression was induced by experimental infection with either CAV or IBDV to assess the effect of immunosuppression on the efficacy of vaccination with Mycoplasma gallisepticum strain ts-304 against infection with virulent M. gallisepticum, a common bacterial pathogen of chickens worldwide. Birds were experimentally infected with either CAV or IBDV at 1 week of age, before vaccination and challenge with M. gallisepticum to examine the effect of immunosuppression at the time of vaccination, or at 6 weeks of age, after vaccination against M. gallisepticum but before challenge with virulent M. gallisepticum, to investigate the effect of immunosuppression at the time of challenge. All birds were vaccinated with a single dose of the ts-304 vaccine at 3 weeks of age and experimentally challenged with the virulent M. gallisepticum strain Ap3AS at 8 weeks of age. In immunosuppressed chickens there was a reduction in protection offered by the ts-304 vaccine at two weeks after challenge, as measured by tracheal mucosal thicknesses, serum antibody levels against M. gallisepticum, air sac lesion scores and virulent M. gallisepticum load in the trachea. Immunosuppressed birds with detectable serum antibodies against M. gallisepticum were less likely to have tracheal lesions. This study has shown that immunosuppression caused by infection with CAV or IBDV can interfere with vaccination against mycoplasmosis in chickens.


Assuntos
Infecções por Birnaviridae/veterinária , Vírus da Anemia da Galinha/imunologia , Galinhas/imunologia , Infecções por Circoviridae/veterinária , Vírus da Doença Infecciosa da Bursa/imunologia , Infecções por Mycoplasma/veterinária , Mycoplasma gallisepticum/imunologia , Doenças das Aves Domésticas/prevenção & controle , Sacos Aéreos/virologia , Animais , Infecções por Birnaviridae/prevenção & controle , Infecções por Birnaviridae/virologia , Vírus da Anemia da Galinha/patogenicidade , Galinhas/microbiologia , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/virologia , Imunidade Celular/imunologia , Imunidade Humoral/imunologia , Imunossupressão/veterinária , Vírus da Doença Infecciosa da Bursa/patogenicidade , Membrana Mucosa/virologia , Infecções por Mycoplasma/microbiologia , Infecções por Mycoplasma/prevenção & controle , Mycoplasma gallisepticum/patogenicidade , Doenças das Aves Domésticas/microbiologia , Traqueia/virologia
16.
Biochem Pharmacol ; 192: 114697, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34302795

RESUMO

The TGF-ß1 cytokine is a key mediator of many biological processes. Complex regulatory mechanisms are in place that allow one single molecule to exert so many distinct indispensable activities. The complexity of TGF-ß1 biology is further illustrated by the opposing dual roles it plays during cancer progression. Risks of toxicities combined with lack of convincing therapeutical efficacy explain at least in part why therapies targeting TGF-ß1 have lagged behind in past decades. However, recent successes of immunostimulatory antibodies for the immunotherapy of cancer and findings that TGF-ß1 activity associates with resistance to immunotherapeutic drugs have revived the field. In this review, we discuss the biology of TGF-ß1 with a special focus on its roles in regulating immune responses in the context of cancer. We describe the various therapeutic approaches available to inhibit TGF-ß signalling, and more recent findings that allow selective targeting of specific sources of TGF-ß activity, which may prove relevant to increase the efficacy and reduce the toxicity of cancer immunotherapy.


Assuntos
Imunidade Celular/imunologia , Imunossupressão/métodos , Imunoterapia/métodos , Neoplasias/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/imunologia , Humanos , Neoplasias/terapia , Estrutura Secundária de Proteína , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/química
17.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203519

RESUMO

Histone acetylation is an epigenetic mechanism that regulates the expression of various genes, such as natural killer group 2, member D (NKG2D) ligands. These NKG2D ligands are the key molecules that activate immune cells expressing the NKG2D receptor. It has been observed that cancer cells overexpress histone deacetylases (HDACs) and show reduced acetylation of nuclear histones. Furthermore, HDAC inhibitors are known to upregulate the expression of NKG2D ligands. Humans have 18 known HDAC enzymes that are divided into four classes. At present, it is not clear which types of HDAC are involved in the expression of NKG2D ligands. We hypothesized that specific types of HDAC genes might be responsible for altering the expression of NKG2D ligands. In this study, we monitored the expression of NKG2D ligands and major histocompatibility complex (MHC) class I molecules in lung cancer cells which were treated with six selective HDAC inhibitors and specific small interfering RNAs (siRNAs). We observed that treatment with FK228, which is a selective HDAC1/2 inhibitor, also known as Romidepsin, induced NKG2D ligand expression at the transcriptional and proteomic levels in two different lung cancer cell lines. It also caused an increase in the susceptibility of NCI-H23 cells to NK cells. Silencing HDAC1 or HDAC2 using specific siRNAs increased NKG2D ligand expression. In conclusion, it appears that HDAC1 and HDAC2 might be the key molecules regulating the expression of NKG2D ligands. These results imply that specifically inhibiting HDAC1 and HDAC2 could induce the expression of NKG2D ligands and improve the NK cell-mediated anti-cancer immunity.


Assuntos
Regulação Neoplásica da Expressão Gênica/imunologia , Histona Desacetilase 1/imunologia , Histona Desacetilase 2/imunologia , Imunidade Celular/imunologia , Neoplasias Pulmonares/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas de Neoplasias/imunologia , Células A549 , Histona Desacetilase 1/genética , Histona Desacetilase 2/genética , Humanos , Células Matadoras Naturais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Proteínas de Neoplasias/genética
18.
Sci Rep ; 11(1): 14917, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290317

RESUMO

We have developed a COVID-19 vaccine, hAd5 S-Fusion + N-ETSD, that expresses SARS-CoV-2 spike (S) and nucleocapsid (N) proteins with modifications to increase immune responses delivered using a human adenovirus serotype 5 (hAd5) platform. Here, we demonstrate subcutaneous (SC) prime and SC boost vaccination of CD-1 mice with this dual-antigen vaccine elicits T-helper cell 1 (Th1) biased T-cell and humoral responses to both S and N that are greater than those seen with hAd5 S wild type delivering only unmodified S. We then compared SC to intranasal (IN) prime vaccination with SC or IN boosts and show that an IN prime with an IN boost is as effective at generating Th1 biased humoral responses as the other combinations tested, but an SC prime with an IN or SC boost elicits greater T cell responses. Finally, we used a combined SC plus IN (SC + IN) prime with or without a boost and found the SC + IN prime alone to be as effective in generating humoral and T-cell responses as the SC + IN prime with a boost. The finding that SC + IN prime-only delivery has the potential to provide broad immunity-including mucosal immunity-against SARS-CoV-2 supports further testing of this vaccine and delivery approach in animal models of viral challenge.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Adenoviridae/genética , Administração Intranasal , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/imunologia , Feminino , Vetores Genéticos , Hipodermóclise , Imunidade Celular/imunologia , Imunidade nas Mucosas/imunologia , Imunização Secundária , Camundongos , Camundongos Endogâmicos , Vacinação/métodos
19.
Curr Rheumatol Rep ; 23(8): 58, 2021 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-34216296

RESUMO

PURPOSE OF REVIEW: In this article, I have reviewed current reports that explore differences and similarities between multisystem inflammatory syndrome in children (MIS-C) and other known multisystem inflammatory diseases seen in children, particularly Kawasaki disease. RECENT FINDINGS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus causing the COVID-19 disease which emerged in China in December 2019 and spread rapidly to the entire country and quickly to other countries. Currently, there is a pandemic of SARS-CoV-2 infection that results in 20% of patients admitted to hospital with illness, with 3% developing intractable acute respiratory distress syndrome (ARDS) with high mortality. However, pediatric COVID-19 is still reported to be a mild disease, affecting only 8% of children. Pathogenesis in children is comparable to adults. There are suggested impaired activation of IFN-alpha and IFN regulator 3, decreased cell response causing impaired viral defense, yet the clinical course is mild, and almost all children recover from the infection without major complications. Interestingly, there is a subset of patients that develop a late but marked immunogenic response to COVID-19 and develop MIS-C. Clinical features of MIS-C resemble certain pediatric rheumatologic diseases, such as Kawasaki disease (mucocutaneous lymph node syndrome) which affects small-medium vessels. Other features of MIS-C resemble those of macrophage activation syndrome (MAS). However, recent research suggests distinct clinical and laboratory differences between MIS-C, Kawasaki disease, and MAS. Since the start of the SARS-CoV-2 pandemic, MIS-C has become the candidate for the most common cause of acquired heart disease in children.


Assuntos
COVID-19/imunologia , Síndrome de Ativação Macrofágica/imunologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , COVID-19/fisiopatologia , Humanos , Imunidade Celular/imunologia , Fator Regulador 3 de Interferon/imunologia , Interferon-alfa/imunologia , Síndrome de Ativação Macrofágica/fisiopatologia , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , SARS-CoV-2 , Índice de Gravidade de Doença , Síndrome de Resposta Inflamatória Sistêmica/fisiopatologia
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