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1.
Proc Natl Acad Sci U S A ; 118(38)2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34470866

RESUMO

Emergence of novel variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need for next-generation vaccines able to elicit broad and durable immunity. Here we report the evaluation of a ferritin nanoparticle vaccine displaying the receptor-binding domain of the SARS-CoV-2 spike protein (RFN) adjuvanted with Army Liposomal Formulation QS-21 (ALFQ). RFN vaccination of macaques using a two-dose regimen resulted in robust, predominantly Th1 CD4+ T cell responses and reciprocal peak mean serum neutralizing antibody titers of 14,000 to 21,000. Rapid control of viral replication was achieved in the upper and lower airways of animals after high-dose SARS-CoV-2 respiratory challenge, with undetectable replication within 4 d in seven of eight animals receiving 50 µg of RFN. Cross-neutralization activity against SARS-CoV-2 variant B.1.351 decreased only approximately twofold relative to WA1/2020. In addition, neutralizing, effector antibody and cellular responses targeted the heterotypic SARS-CoV-1, highlighting the broad immunogenicity of RFN-ALFQ for SARS-CoV-like Sarbecovirus vaccine development.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/virologia , Macaca mulatta/imunologia , Nanopartículas/química , Receptores Virais/metabolismo , SARS-CoV-2/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Ferritinas/química , SARS-CoV-2/metabolismo , Linfócitos T/imunologia
2.
Anticancer Res ; 41(9): 4515-4522, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475077

RESUMO

BACKGROUND/AIM: The role of tumour-infiltrating CD45Ro+ T-cells in oral squamous cell carcinoma (OSCC) is unclear. This study aimed to evaluate prognostic biomarkers for OSCC. PATIENTS AND METHODS: We determined the density of tumour-infiltrating CD45Ro+ T cells in the parenchyma and stroma at the tumour centre (TCe) and invasive front (IF) and examined the association between the density of these cells and histopathological status in 142 patients. RESULTS: Five-year overall survival (OS) and recurrence-free survival were favourable in patients with high CD45Ro+ T-cell density in the TCe stroma. OS was favourable in patients with high CD45Ro+ T-cell density in the IF stroma. Stepwise Cox regression model analysis indicated that CD45Ro+ T-cells in the stroma of the IF and TCe were an independent prognostic factor for OS. CONCLUSION: CD45Ro+ T-cells in the stroma of the IF and TCe play a role in cancer immune surveillance and may be a useful prognostic factor.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Antígenos Comuns de Leucócito/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Bucais/mortalidade , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/imunologia , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Análise de Sobrevida
3.
Nat Commun ; 12(1): 5215, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471122

RESUMO

Achieving sufficient worldwide vaccination coverage against SARS-CoV-2 will require additional approaches to currently approved viral vector and mRNA vaccines. Subunit vaccines may have distinct advantages when immunizing vulnerable individuals, children and pregnant women. Here, we present a new generation of subunit vaccines targeting viral antigens to CD40-expressing antigen-presenting cells. We demonstrate that targeting the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to CD40 (αCD40.RBD) induces significant levels of specific T and B cells, with long-term memory phenotypes, in a humanized mouse model. Additionally, we demonstrate that a single dose of the αCD40.RBD vaccine, injected without adjuvant, is sufficient to boost a rapid increase in neutralizing antibodies in convalescent non-human primates (NHPs) exposed six months previously to SARS-CoV-2. Vaccine-elicited antibodies cross-neutralize different SARS-CoV-2 variants, including D614G, B1.1.7 and to a lesser extent B1.351. Such vaccination significantly improves protection against a new high-dose virulent challenge versus that in non-vaccinated convalescent animals.


Assuntos
Antígenos CD40/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos B/imunologia , Convalescença , Humanos , Macaca , Camundongos , Mutação , Domínios Proteicos , Reinfecção/prevenção & controle , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T/imunologia , Vacinação , Vacinas de Subunidades/imunologia
4.
Nat Commun ; 12(1): 5090, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429421

RESUMO

CRISPR-Cas9 mediated genome editing offers unprecedented opportunities for treating human diseases. There are several reports that demonstrate pre-existing immune responses to Cas9 which may have implications for clinical development of CRISPR-Cas9 mediated gene therapy. Here we use 209 overlapping peptides that span the entire sequence of Staphylococcus aureus Cas9 (SaCas9) and human peripheral blood mononuclear cells (PBMCs) from a cohort of donors with a distribution of Major Histocompatibility Complex (MHC) alleles comparable to that in the North American (NA) population to identify the immunodominant regions of the SaCas9 protein. We also use an MHC Associated Peptide Proteomics (MAPPs) assay to identify SaCas9 peptides presented by MHC Class II (MHC-II) proteins on dendritic cells. Using these two data sets we identify 22 SaCas9 peptides that are both presented by MHC-II proteins and stimulate CD4+ T-cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Sistemas CRISPR-Cas , Proliferação de Células/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Sequência de Aminoácidos , Proteína 9 Associada à CRISPR/genética , Citocinas , Edição de Genes , Humanos , Staphylococcus aureus/genética , Linfócitos T/imunologia
5.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445605

RESUMO

Coronavirus disease (COVID-19) is a contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This case report presents a patient who had difficulty eradicating the corona virus due to being treated with Rituximab, which depletes B lymphocyte cells and therefore disables the production of neutralizing antibodies. The combined use of external anti-viral agents like convalescent plasma, IVIG and Remdesivir successfully helped the patient's immune system to eradicate the virus without B-cell population recovery. In vitro studies showed that convalescent plasma is the main agent that helped in eradicating the virus.


Assuntos
Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/terapia , SARS-CoV-2/imunologia , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Anticorpos Neutralizantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico por imagem , Chlorocebus aethiops , Humanos , Imunização Passiva , Hospedeiro Imunocomprometido , Rituximab/uso terapêutico , Linfócitos T/imunologia , Células Vero
6.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360833

RESUMO

CD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer.


Assuntos
Antígenos CD/metabolismo , Apirase/metabolismo , Linfócitos T/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos CD/fisiologia , Apirase/genética , Apirase/imunologia , Apirase/fisiologia , Regulação da Expressão Gênica , Humanos , Linfócitos T/imunologia
7.
Nat Commun ; 12(1): 5023, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34408144

RESUMO

T cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-µbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αß T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-µbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Células-Tronco Hematopoéticas/citologia , Linfopoese , Doenças da Imunodeficiência Primária/terapia , Linfócitos T/citologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antígenos CD34/genética , Antígenos CD34/imunologia , Proteínas de Ligação ao Cálcio/genética , Linhagem da Célula , Terapia Baseada em Transplante de Células e Tecidos , Células Cultivadas , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/imunologia , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/imunologia , Doenças da Imunodeficiência Primária/fisiopatologia , Linfócitos T/imunologia , Linfócitos T/transplante
8.
Front Immunol ; 12: 721738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456929

RESUMO

Here, we described the case of a B cell-deficient patient after CD19 CAR-T cell therapy for refractory B cell Non-Hodgkin Lymphoma with protracted coronavirus disease 2019 (COVID-19). For weeks, this patient only inefficiently contained the virus while convalescent plasma transfusion correlated with virus clearance. Interestingly, following convalescent plasma therapy natural killer cells matured and virus-specific T cells expanded, presumably allowing virus clearance and recovery from the disease. Our findings, thus, suggest that convalescent plasma therapy can activate cellular immune responses to clear SARS-CoV-2 infections. If confirmed in larger clinical studies, these data could be of general importance for the treatment of COVID-19 patients.


Assuntos
Linfócitos B , COVID-19/imunologia , COVID-19/terapia , Síndromes de Imunodeficiência/imunologia , Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Linfócitos B/imunologia , COVID-19/complicações , Feminino , Humanos , Imunização Passiva , Imunoglobulinas Intravenosas , Síndromes de Imunodeficiência/complicações , Ativação Linfocitária , Linfopoese , SARS-CoV-2 , Carga Viral
9.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360889

RESUMO

Despite extensive research, there is still no vaccine against the hepatitis C virus (HCV). The aim of this study was to investigate whether MSCs can exhibit adjuvant properties during DNA vaccination against hepatitis C. We used the pcNS3-NS5B plasmid encoding five nonstructural HCV proteins and MSCs derived from mice bone marrow. Five groups of DBA mice were immunized with the plasmid and/or MSCs in a different order. Group 1 was injected with the plasmid twice at intervals of 3 weeks; Group 2 with the plasmid, and after 24 h with MSCs; Group 3 with MSCs followed by the plasmid the next day; Group 4 with only MSCs; and Group 5 with saline. When the MSCs were injected prior to DNA immunization, the cell immune response to HCV proteins assessed by the level of IFN-γ synthesis was markedly increased compared to DNA alone. In contrast, MSCs injected after DNA suppressed the immune response. Apparently, the high level of proinflammatory cytokines detected after DNA injection promotes the conversion of MSCs introduced later into the immunosuppressive MSC2. The low level of cytokines in mice before MSC administration promotes the high immunostimulatory activity of MSC1 in response to a DNA vaccine. Thus, when administered before DNA, MSCs are capable of exhibiting promising adjuvant properties.


Assuntos
Genes Virais/imunologia , Hepacivirus/genética , Hepacivirus/imunologia , Hepatite C/prevenção & controle , Imunidade Celular , Células-Tronco Mesenquimais/imunologia , Vacinação/métodos , Vacinas de DNA/administração & dosagem , Proteínas não Estruturais Virais/genética , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Camundongos , Camundongos Endogâmicos DBA , Plasmídeos/genética , Linfócitos T/imunologia , Transfecção , Resultado do Tratamento , Vacinas de DNA/imunologia
10.
Cells ; 10(7)2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34359987

RESUMO

Since the end of 2019, a new, dangerous virus has caused the deaths of more than 3 million people. Efforts to fight the disease remain multifaceted and include prophylactic strategies (vaccines), the development of antiviral drugs targeting replication, and the mitigation of the damage associated with exacerbated immune responses (e.g., interleukin-6-receptor inhibitors). However, numerous uncertainties remain, making it difficult to lower the mortality rate, especially among critically ill patients. While looking for a new means of understanding the pathomechanisms of the disease, we asked a question-is our immunity key to resolving these uncertainties? In this review, we attempt to answer this question, and summarize, interpret, and discuss the available knowledge concerning the interplay between neutrophils, neutrophil extracellular traps (NETs), and T-cells in COVID-19. These are considered to be the first line of defense against pathogens and, thus, we chose to emphasize their role in SARS-CoV-2 infection. Although immunologic alterations are the subject of constant research, they are poorly understood and often underestimated. This review provides background information for the expansion of research on the novel, immunity-oriented approach to diagnostic and treatment possibilities.


Assuntos
COVID-19/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Animais , COVID-19/diagnóstico , COVID-19/patologia , COVID-19/terapia , Humanos , Imunidade Inata , Neutrófilos/patologia , Linfócitos T/patologia
11.
Nat Commun ; 12(1): 4907, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389726

RESUMO

The intestinal mucosa constitutes an environment of closely regulated immune cells. Dendritic cells (DC) interact with the gut microbiome and antigens and are important in maintaining gut homeostasis. Here, we investigate DC transcriptome, phenotype and function in five anatomical locations of the gut lamina propria (LP) which constitute different antigenic environments. We show that DC from distinct gut LP compartments induce distinct T cell differentiation and cytokine secretion. We also find that PD-L1+ DC in the duodenal LP and XCR1+ DC in the colonic LP comprise distinct tolerogenic DC subsets that are crucial for gut homeostasis. Mice lacking PD-L1+ and XCR1+ DC have a proinflammatory gut milieu associated with an increase in Th1/Th17 cells and a decrease in Treg cells and have exacerbated disease in the models of 5-FU-induced mucositis and DSS-induced colitis. Our findings identify PD-L1+ and XCR1+ DC as region-specific physiologic regulators of intestinal homeostasis.


Assuntos
Antígeno B7-H1/imunologia , Células Dendríticas/imunologia , Homeostase/imunologia , Mucosa Intestinal/imunologia , Receptores de Quimiocinas/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Colite/genética , Colite/imunologia , Colite/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/genética , Microbioma Gastrointestinal/imunologia , Homeostase/genética , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma/genética , Transcriptoma/imunologia
12.
J Immunol ; 207(4): 1150-1164, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34341167

RESUMO

CARD11 is a multidomain scaffold protein required for normal activation of NF-κB, JNK, and mTOR during Ag receptor signaling. Germline CARD11 mutations cause at least three types of primary immunodeficiency including CARD11 deficiency, B cell expansion with NF-κB and T cell anergy (BENTA), and CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS). CADINS is uniquely caused by heterozygous loss-of-function CARD11 alleles that act as dominant negatives. CADINS patients present with frequent respiratory and skin infections, asthma, allergies, and atopic dermatitis. However, precisely how a heterozygous dominant negative CARD11 allele leads to the development of this CADINS-specific cluster of symptoms remains poorly understood. To address this, we generated mice expressing the CARD11 R30W allele originally identified in patients. We find that CARD11R30W/+ mice exhibit impaired signaling downstream of CARD11 that leads to defects in T, B, and NK cell function and immunodeficiency. CARD11R30W/+ mice develop elevated serum IgE levels with 50% penetrance that becomes more pronounced with age, but do not develop spontaneous atopic dermatitis. CARD11R30W/+ mice display reduced regulatory T cell numbers, but not the Th2 expansion observed in other mice with diminished CARD11 activity. Interestingly, the presence of mixed CARD11 oligomers in CARD11R30W/+ mice causes more severe signaling defects in T cells than in B cells, and specifically impacts IFN-γ production by NK cells, but not NK cell cytotoxicity. Our findings help explain the high susceptibility of CADINS patients to infection and suggest that the development of high serum IgE is not sufficient to induce overt atopic symptoms.


Assuntos
Linfócitos B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Imunoglobulina E/imunologia , Células Matadoras Naturais/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Alelos , Animais , Heterozigoto , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL
13.
Nat Commun ; 12(1): 4734, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354077

RESUMO

The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.


Assuntos
Melanoma Experimental/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Técnicas de Reprogramação Celular/métodos , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Feminino , Vetores Genéticos , Interleucina-33/deficiência , Interleucina-33/genética , Interleucina-33/imunologia , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/imunologia , Vírus da Coriomeningite Linfocítica/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células Estromais/imunologia , Células Estromais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Microambiente Tumoral/imunologia
14.
Sci Rep ; 11(1): 15927, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354210

RESUMO

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range. We applied single-cell RNA-sequencing and measured the cellular composition and transcriptional profile of the nasal mucosa in 35 SARS-CoV-2 negative children and adults, ranging in age from 4 months to 65 years. We analyzed in total of ~ 30,000 immune and epithelial cells and found that age and immune cell proportion in the nasal mucosa are inversely correlated, with little evidence for structural changes in the transcriptional state of a given cell type across the age range. Orthogonal validation by epigenome sequencing indicate that it is especially cells of the innate immune system that underlie the age-association. Additionally, we characterize the predominate immune cell type in the nasal mucosa: a resident T cell like population with potent antiviral properties. These results demonstrate fundamental changes in the immune cell makeup of the uninfected nasal mucosa over the lifespan. The resource we generate here is an asset for future studies focusing on respiratory infection and immunization strategies.


Assuntos
COVID-19/imunologia , Mucosa Nasal/imunologia , SARS-CoV-2/imunologia , Adolescente , Adulto , COVID-19/genética , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Celular , Imunidade Inata , Lactente , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/citologia , Mucosa Nasal/metabolismo , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Adulto Jovem
15.
Blood Cancer J ; 11(8): 142, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376633

RESUMO

This study evaluated the safety and immunogenicity of BNT162b2 vaccine in patients with hematological malignancies. Antibodies blocking spike binding to immobilized ACE-2 (NAb) correlated with anti-Spike (S) IgG d42 titers (Spearman r = 0.865, p < 0.0001), and an anti-S IgG d42 level ≥3100 UA/mL was predictive of NAb ≥ 30%, the positivity cutoff for NAb (p < 0.0001). Only 47% of the patients achieved an anti-S IgG d42 level ≥3100 UA/mL after the two BNT162b2 inocula, compared to 87% of healthy controls. In multivariable analysis, male patients, use of B-cell targeting treatment within the last 12 months prior to vaccination, and CD19+ B-cell level <120/uL, were associated with a significantly decreased probability of achieving a protective anti-S IgG level after the second BNT162b2 inoculum. Finally, using the IFN-γ ELISPOT assay, we found a significant increase in T-cell response against the S protein, with 53% of patients having an anti-S IgG-positive ELISPOT after the second BNT162b2 inoculum. There was a correlation between the anti-S ELISPOT response and IgG d42 level (Spearman r = 0.3026, p = 0.012). These findings suggest that vaccination with two BNT162b2 inocula translates into a significant increase in humoral and cellular response in patients with hematological malignancies, but only around half of the patients can likely achieve effective immune protection against COVID-19.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/complicações , COVID-19/imunologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Imunogenicidade da Vacina , SARS-CoV-2/imunologia , Imunidade Adaptativa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra COVID-19/administração & dosagem , Comorbidade , Feminino , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
16.
Nat Commun ; 12(1): 5074, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417463

RESUMO

ß cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human ß cells with inflammation but its expression is reduced in surviving ß cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate ß cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO ß cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between ß cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in ß cells may reduce activating pathologic immune cells and killing of ß cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/patologia , Inflamação/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteínas Proto-Oncogênicas/metabolismo , Animais , Sequência de Bases , Citotoxicidade Imunológica , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Humanos , Imunidade , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Linfócitos T/imunologia , Transcrição Genética
17.
Nat Commun ; 12(1): 5061, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404775

RESUMO

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.


Assuntos
Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Monoclonais/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteínas de Transporte , Epitopos , Humanos , Imunidade , SARS-CoV-2/efeitos dos fármacos , Linfócitos T/imunologia
18.
Clin Immunol ; 230: 108817, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34352391

RESUMO

Many studies have analyzed myelin-reactivity of T cells in multiple sclerosis (MS); however, with conflicting results. In this study we compare methods to determine myelin reactivity of T cells and aim to delineate the cause of inconsistency in the literature. Challenging T cells with myelin antigens we found a significant increase in antigen-reactivity of T cells from patients with MS using an ELISpot-assay, in contrast to a CFSE-dilution assay. Comparing the two assays showed that the myelin-reactive T cells detected in the ELISpot-assay originated primarily from effector memory T cells in contrast to the myelin-reactive T cells of the CFSE-assay representing a population of both naïve, central memory and effector memory T cells. This diversity in T cell populations activated in the two assays likely contribute to the discrepancy found in the literature and encourages thorough considerations when choosing an assay to determine antigen-specificity of T cells in future studies.


Assuntos
Imunoensaio/métodos , Esclerose Múltipla Recidivante-Remitente/imunologia , Proteínas da Mielina/imunologia , Linfócitos T/imunologia , Adulto , Autoantígenos/imunologia , Estudos de Casos e Controles , ELISPOT , Feminino , Fluoresceínas , Corantes Fluorescentes , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Proteína Básica da Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Succinimidas , Linfócitos T/classificação , Adulto Jovem
19.
Eur Rev Med Pharmacol Sci ; 25(15): 5057-5062, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355378

RESUMO

OBJECTIVE: Complete blood count parameters are frequently altered in COVID-19 patients. Leucopenia and lymphopenia are the most common findings. This is not specific to COVID-19 as similar alterations are found in various other viral infections. This work is intended to summarize the evidence regarding white blood cell and lymphocyte subset alterations in COVID-19 and their clinical implications. MATERIALS AND METHODS: A PubMed search was conducted to identify relevant original studies. Articles not available in English or referring exclusively to pediatric patients were excluded. The study was designed as a narrative review from its inception. RESULTS: Complete white blood cell number and lymphocytes may be reduced in COVID-19 patients. Circulating CD4+ cells (helper T lymphocytes), CD8+ cells (cytotoxic T lymphocytes), regulatory T cells and natural killer (NK) cells may be reduced, with a greater reduction observed in critically ill patients. CD4+ and regulatory cell deficiencies may contribute to the cytokine storm and subsequent tissue damage observed in severe COVID-19 infection. NK and CD8+ cell deficiency might delay infection clearance. These aberrations of cellular immunity may contribute significantly to the pathogenesis of the disease. Alterations observed in monocyte function can also be implicated as they are effector cells responsible for tissue damage and remodeling. B cell dysfunction and maturation abnormalities have also been reported, suggesting that the virus also impairs humoral immunity. CONCLUSIONS: Lymphocyte subset abnormalities may be useful prognostic biomarkers for COVID-19, with circulating CD8+ cell count being the most promising as a predictor of severe disease requiring mechanical ventilation and mortality.


Assuntos
COVID-19/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/virologia , Monócitos/imunologia , Monócitos/virologia , Linfócitos B/imunologia , Linfócitos B/virologia , COVID-19/virologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Linfócitos T/imunologia , Linfócitos T/virologia
20.
Front Immunol ; 12: 719077, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394127

RESUMO

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is a major global public threat. Currently, a worldwide effort has been mounted to generate billions of effective SARS-CoV-2 vaccine doses to immunize the world's population at record speeds. However, there is still a demand for alternative effective vaccines that rapidly confer long-term protection and rely upon cost-effective, easily scaled-up manufacturing. Here, we present a Sindbis alphavirus vector (SV), transiently expressing the SARS-CoV-2 spike protein (SV.Spike), combined with the OX40 immunostimulatory antibody (αOX40) as a novel, highly effective vaccine approach. We show that SV.Spike plus αOX40 elicits long-lasting neutralizing antibodies and a vigorous T-cell response in mice. Protein binding, immunohistochemical, and cellular infection assays all show that vaccinated mice sera inhibits spike functions. Immunophenotyping, RNA Seq transcriptome profiles, and metabolic analysis indicate a reprogramming of T cells in vaccinated mice. Activated T cells were found to mobilize to lung tissue. Most importantly, SV.Spike plus αOX40 provided robust immune protection against infection with authentic coronavirus in transgenic mice expressing the human ACE2 receptor (hACE2-Tg). Finally, our immunization strategy induced strong effector memory response, potentiating protective immunity against re-exposure to SARS-CoV-2 spike protein. Our results show the potential of a new Sindbis virus-based vaccine platform to counteract waning immune response, which can be used as a new candidate to combat SARS-CoV-2. Given the T-cell responses elicited, our vaccine is likely to be effective against variants that are proving challenging, as well as serve as a platform to develop a broader spectrum pancoronavirus vaccine. Similarly, the vaccine approach is likely to be applicable to other pathogens.


Assuntos
Antígenos de Diferenciação/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vírus Sindbis/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Cricetinae , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vírus Sindbis/genética , Linfócitos T/imunologia , Vacinação
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