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1.
Biomed Res Int ; 2020: 2854186, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33015160

RESUMO

Objectives: To evaluate the role of short-term low-dose glucocorticoids in mild COVID-19 patients. Methods: We conducted a retrospective, cross-sectional, single-center study in Kunming, China. A total of 33 mild COVID-19 cases were divided into two treatment groups (with and without glucocorticoids, methylprednisolone, were used in this setting), and the absolute value of peripheral blood lymphocyte count; CD3+, CD4+, and CD8+ T cell counts; and the time to achieve negative transformation of a nucleic acid pharyngeal swab were recorded. Peripheral blood lymphocyte and T cell counts were compared between the treatment group and 25 healthy individuals. At the point of time when there was a 50% accumulation conversion rate (positive to negative nucleic acid on pharyngeal swab), and the nucleic acid turned negative in half of the patients in two groups, the peripheral blood lymphocyte and T cell counts were compared between treatment groups. Results: The mean cumulative time for the 50% negative conversion rate of the nucleic acid in the pharyngeal swab was 17.7 ± 5.1 days and 13.9 ± 5.4 days in the glucocorticoid group and the nonglucocorticoid group, respectively. The absolute peripheral blood lymphocyte count and the T cell subset count in the glucocorticoid group were lower than those in the nonglucocorticoid group. When the nucleic acid turned negative in half of the patients, the absolute value of peripheral blood lymphocyte count and CD4+ T cells of the glucocorticoid group and the nonglucocorticoid group was not significantly different; the CD3+ and CD8+ T cells in the glucocorticoid group were lower than those in the nonglucocorticoid group. The absolute peripheral blood lymphocyte count, CD3+ T cells, and CD4+ T cells in the glucocorticoid group were lower than those of the healthy group during the whole disease period, and CD8+ T cells returned to normal at 19-21 days of the disease period. There was no significant difference between the nonglucocorticoid group and the healthy group for absolute peripheral blood lymphocyte and CD8+ T cells; moreover, CD3+ T cells and CD4+ T cells were lower in the nonglucocorticoid group than those in the healthy group from the day of admission to the 18th day and returned to normal at the period of 19-21 days. The absolute peripheral lymphocyte count (P = 0.048, effect size d = 0.727) and T cell subset count (CD3: P = 0.042, effect size d = 0.655; CD4: P < 0.01, effect size d = 0.599; and CD8: P = 0.034, effect size d = 0.550) in the nonglucocorticoid group were higher than those in the glucocorticoid group, and the difference between the groups was statistically significant. Conclusions: This study found that the use of short-term, low-dose glucocorticoids does not negatively influence the clinical outcome, without affecting the final clearance of viral nucleic acid in mild COVID-19 patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Adolescente , Adulto , Betacoronavirus/isolamento & purificação , Criança , China/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estudos Transversais , Feminino , Humanos , Contagem de Linfócitos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Estudos Retrospectivos , Subpopulações de Linfócitos T/imunologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Medicine (Baltimore) ; 99(41): e22568, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031305

RESUMO

The effect of intraoperative blood transfusion on the immune function and prognosis of hepatocellular carcinoma (HCC) has not been fully investigated. The aim of this study was to evaluate the effects of intraoperative autologous blood transfusion and allogeneic blood transfusion on immune function and prognosis in surgically treated HCC patients. One hundred fourteen primary hepatic carcinoma patients who would undergo selective operations were divided into two groups, 35 patients in the experimental group received intraoperative autologous blood transfusion and 79 patients in the control group received allogeneic blood transfusion. The amount of serum T lymphocyte subsets, natural killer (NK) cells and immunoglobulin before and after operation, as well as the recurrence-free survival (RFS) were compared. Results shown that, there was no significant difference in the level of immunocytes and immunoglobulin between the two groups before treatment (P > .05). At 1 day after surgery, there were significant differences in T lymphocyte, NK cells and immunoglobulin levels before and after transfusion. CD3+, CD4+, CD4+/CD8+, and NK cells in autologous transfusion group were significantly higher than those in allogeneic transfusion group (P < .05); the level of IgG, IgM, and IgA in allogeneic transfusion group were significantly lower than those before operation (P < .05), the level of IgG, IgM, and IgA in autologous transfusion group did not significantly fluctuate, and significantly higher than those of allogeneic transfusion group (P < .05). At 5 days after surgery, all indexes of autologous transfusion group recovered to the preoperative level, the levels of CD3+, CD4+, CD4+/CD8+, NK cells, IgG, IgM, and IgA were significantly higher than those of allogeneic transfusion group (P < .05). The follow-up results showed that the RFS of autologous transfusion group was significantly higher than that of allogeneic transfusion group (P < .05). In conclusion, compared with allogeneic blood transfusion, intraoperative autologous blood transfusion possessed less impact on immune function, it may even improve immune function and RFS in HCC patients after surgery. Therefore, HCC patients should be recommended to receive autologous blood transfusion instead of allogeneic blood transfusion when they need blood transfusion during the perioperative period.


Assuntos
Transfusão de Sangue , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/cirurgia , Cuidados Intraoperatórios , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/cirurgia , Transfusão de Sangue Autóloga , Feminino , Humanos , Imunoglobulinas/imunologia , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Subpopulações de Linfócitos T/imunologia
3.
Anticancer Res ; 40(9): 4875-4883, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878775

RESUMO

BACKGROUND/AIM: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses. MATERIALS AND METHODS: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs. RESULTS: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs. CONCLUSION: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.


Assuntos
Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Imunoterapia/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Idoso , Antineoplásicos Imunológicos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Perfilação da Expressão Gênica , Genes Codificadores dos Receptores de Linfócitos T/genética , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia
5.
mBio ; 11(5)2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948688

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8+ T cell subsets. PD-1-expressing CD8+ T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.IMPORTANCE Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.


Assuntos
Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Linfócitos T Citotóxicos/patologia , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Betacoronavirus/patogenicidade , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Citotoxinas/metabolismo , Feminino , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Linfócitos T Citotóxicos/imunologia
6.
Front Immunol ; 11: 2160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983180

RESUMO

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide. Measuring the prevention and control of the disease has become a matter requiring urgent focus. Objective: Based on coronavirus disease 2019 (COVID-19) clinical data from Wuhan, we conducted an in-depth analysis to clarify some of the pathological mechanisms of the disease and identify simple measures to predict its severity early on. Methods: A total of 230 patients with non-mild COVID-19 were recruited, and information on their clinical characteristics, inflammatory cytokines, and T lymphocyte subsets was collected. Risk factors for severity were analyzed by binary logistic regression, and the associations of neutrophil-to-lymphocyte ratios (N/LRs) with illness severity, disease course, CT grading, inflammatory cytokines, and T lymphocyte subsets were evaluated. Results: Our results showed that the N/LRs were closely related to interleukin (IL)-6 and IL-10 (P < 0.001, P = 0.024) and to CD3+ and CD8+ T lymphocytes (P < 0.001, P = 0.046). In particular, the N/LRs were positively correlated with the severity and course of the disease (P = 0.021, P < 0.001). Compared to the values at the first test after admission, IL-6 and IL-10 were significantly decreased and increased, respectively, as of the last test before discharge (P = 0.006, P < 0.001). More importantly, through binary logistic regression, we found that male sex, underlying diseases (such as cardiovascular disease), pulse, and N/LRs were all closely related to the severity of the disease (P = 0.004, P = 0.012, P = 0.013, P = 0.028). Conclusions: As a quick and convenient marker of inflammation, N/LRs may predict the disease course and severity level of non-mild COVID-19; male sex, cardiovascular disease, and pulse are also risk factors for the severity of non-mild COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Neutrófilos/imunologia , Pneumonia Viral/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Biomarcadores , Doenças Cardiovasculares , Infecções por Coronavirus/virologia , Feminino , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Pulso Arterial , Fatores de Risco , Fatores Sexuais
7.
Anticancer Res ; 40(9): 5221-5227, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878810

RESUMO

BACKGROUND/AIM: Bladder cancer (BLCA, urothelial bladder cancer) is one of the most common malignancies with increasing incidence and mortality worldwide. Poor diagnosis and the limitation of treatment is still an unmet need in clinical practice. γδ T-Cells have been paid increasing attention because of their potent cytotoxicity against tumors. Herein, we investigated the cytolytic effect of γδ T-cells in combination with the chemotherapeutic drug, carboplatin, against BLCA cells. MATERIALS AND METHODS: The standard protocol for the induction and expansion of peripheral blood mononuclear cell-derived γδ T-cells was a zoledronic acid/interleukin-2-based medium system for 2 weeks. The cytotoxicity of γδ T-cells with and without carboplatin against BLCA cells was examined. RESULTS: After incubation, T-cell receptor-positive γδ T-cells showed a natural killer cell-like phenotypic characteristic and dose-dependently increased cytotoxicity against BLCA cells. Interestingly, we found that in advanced BLCA cells, which were more resistant to carboplatin, the cell viability was significantly (p<0.05) reduced in the presence of γδ T-cells. CONCLUSION: Our findings showed that γδ T-cell therapy has potent benefit in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias da Bexiga Urinária/patologia
8.
Science ; 369(6503)2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732394

RESUMO

The lymphoid system is intimately involved in immunological processes. The small lymphocyte that circulates through blood into lymphoid tissues, then through the lymph and back to the blood through the thoracic duct, is able to initiate immune responses after appropriate stimulation by antigen. However, the lymphocytes found in the thymus are deficient in this ability despite the fact that the thymus plays a central role in lymphocyte production and in ensuring the normal development of immunological faculty. During embryogenesis, lymphocytes are present in the thymus before they can be identified in the circulation and in other lymphoid tissues. They become "educated" in the thymus to recognize a great diversity of peptide antigens bound to the body's own marker antigen, the major histocompatibility complex, but they are purged if they strongly react against their own self-components. Lymphocytes differentiate to become various T cell subsets and then exit through the bloodstream to populate certain areas of the lymphoid system as peripheral T lymphocytes with distinct markers and immune functions.


Assuntos
Imunoterapia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Linfócitos B/imunologia , Diferenciação Celular , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Linfoma/imunologia , Linfoma/terapia , Camundongos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Transplante de Pele , Subpopulações de Linfócitos T/citologia , Timo/citologia
9.
Ann Hematol ; 99(10): 2215-2229, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32856140

RESUMO

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos CD19/imunologia , Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Corticosteroides/uso terapêutico , Adulto , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/economia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Ensaios Clínicos como Assunto , Terapia Combinada , Análise Custo-Benefício , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Custos de Medicamentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/economia , Infusões Intravenosas , Injeções Subcutâneas , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pré-Medicação , Qualidade de Vida , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento , Carga Tumoral , Evasão Tumoral
11.
Science ; 369(6505): 818-823, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32616673

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic. It is unclear whether convalescing patients have a risk of reinfection. We generated a rhesus macaque model of SARS-CoV-2 infection that was characterized by interstitial pneumonia and systemic viral dissemination mainly in the respiratory and gastrointestinal tracts. Rhesus macaques reinfected with the identical SARS-CoV-2 strain during the early recovery phase of the initial SARS-CoV-2 infection did not show detectable viral dissemination, clinical manifestations of viral disease, or histopathological changes. Comparing the humoral and cellular immunity between primary infection and rechallenge revealed notably enhanced neutralizing antibody and immune responses. Our results suggest that primary SARS-CoV-2 exposure protects against subsequent reinfection in rhesus macaques.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Canal Anal/virologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Subpopulações de Linfócitos B/imunologia , Betacoronavirus/imunologia , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Modelos Animais de Doenças , Interações entre Hospedeiro e Microrganismos , Imunidade Celular , Imunidade Humoral , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/virologia , Macaca mulatta , Nasofaringe/virologia , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Recidiva , Subpopulações de Linfócitos T/imunologia , Carga Viral , Replicação Viral
12.
Nat Commun ; 11(1): 3434, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632085

RESUMO

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients' T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Senescência Celular , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Humanos , Memória Imunológica , Itália/epidemiologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
13.
Proc Natl Acad Sci U S A ; 117(31): 18638-18648, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32665435

RESUMO

Vγ9Vδ2 T cells are a major human blood γδ T cell population that respond in a T cell receptor (TCR)-dependent manner to phosphoantigens which are generated by a variety of microorganisms. It is not clear how Vγ9Vδ2 T cells react toward the sudden microbial exposure early after birth. We found that human Vγ9Vδ2 T cells with a public/shared fetal-derived TCR repertoire expanded within 10 wk postpartum. Such an expansion was not observed in non-Vγ9Vδ2 γδ T cells, which possessed a private TCR repertoire. Furthermore, only the Vγ9Vδ2 T cells differentiated into potent cytotoxic effector cells by 10 wk of age, despite their fetal origin. Both the expansion of public fetal Vγ9Vδ2 T cells and their functional differentiation were not affected by newborn vaccination with the phosphoantigen-containing bacillus Calmette-Guérin (BCG) vaccine. These findings suggest a strong and early priming of the public fetal-derived Vγ9Vδ2 T cells promptly after birth, likely upon environmental phosphoantigen exposure.


Assuntos
Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Vacina BCG/imunologia , Células Cultivadas , Citocinas/metabolismo , Feminino , Feto/imunologia , Humanos , Lactente , Recém-Nascido , Gravidez
14.
Proc Natl Acad Sci U S A ; 117(31): 18649-18660, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690687

RESUMO

Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal γδ T cell repertoires are shaped by microbial exposure after birth, we monitored the γ-chain (TRG) and δ-chain (TRD) repertoires of peripheral blood T cells in newborns, infants, and young children from Europe and sub-Saharan Africa. We identified a set of TRG and TRD sequences that were shared by all children from Europe and Africa. These were primarily public clones, characterized by simple rearrangements of Vγ9 and Vδ2 chains with low junctional diversity and usage of non-TRDJ1 gene segments, reminiscent of early ontogenetic subsets of γδ T cells. Further profiling revealed that these innate, public Vγ9Vδ2+ T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, γδ T cells using Vδ1+ and Vδ3+ TRD rearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of Vδ1+ and Vδ3+ TRD sequences in the majority of African children. In summary, we show how dynamic γδ TCR repertoires develop directly after birth and present important differences among γδ T cell subsets.


Assuntos
Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T/imunologia , África ao Sul do Saara , Bactérias/imunologia , Criança , Pré-Escolar , Europa (Continente) , Rearranjo Gênico do Linfócito T/genética , Rearranjo Gênico do Linfócito T/imunologia , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia
15.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32612152

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia Viral/imunologia , Pneumonia/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/genética , Apirase/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
16.
JCI Insight ; 5(17)2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32687484

RESUMO

COVID-19-associated morbidity and mortality have been attributed to a pathologic host response. Two divergent hypotheses have been proposed: hyperinflammatory cytokine storm; and failure of host protective immunity that results in unrestrained viral dissemination and organ injury. A key explanation for the inability to address this controversy has been the lack of diagnostic tools to evaluate immune function in COVID-19 infections. ELISpot, a highly sensitive, functional immunoassay, was employed in 27 patients with COVID-19, 51 patients with sepsis, 18 critically ill nonseptic (CINS) patients, and 27 healthy control volunteers to evaluate adaptive and innate immune status by quantitating T cell IFN-É£ and monocyte TFN-α production. Circulating T cell subsets were profoundly reduced in COVID-19 patients. Additionally, stimulated blood mononuclear cells produced less than 40%-50% of the IFN-É£ and TNF-α observed in septic and CINS patients, consistent with markedly impaired immune effector cell function. Approximately 25% of COVID-19 patients had increased IL-6 levels that were not associated with elevations in other canonical proinflammatory cytokines. Collectively, these findings support the hypothesis that COVID-19 suppresses host functional adaptive and innate immunity. Importantly, IL-7 administered ex vivo restored T cell IFN-É£ production in COVID-19 patients. Thus, ELISpot may functionally characterize host immunity in COVID-19 and inform prospective therapies.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Sepse/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Estudos de Casos e Controles , Estado Terminal , ELISPOT , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Pandemias , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
17.
Science ; 369(6504): 718-724, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32661059

RESUMO

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon alfa-2/metabolismo , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Pneumonia Viral/imunologia , Adulto , Idoso , Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Estado Terminal , Estudos Transversais , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
18.
J Vis Exp ; (160)2020 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-32658200

RESUMO

T Follicular Helper (Tfh) cells are an independent CD4+ T cell subset specialized in providing help for germinal center (GC) development and generation of high-affinity antibodies. In influenza virus infection, robust Tfh and GC B cell responses are induced to facilitate effective virus eradication, which confers a qualified mouse model for Tfh-associated study. In this paper, we described protocols in detection of basic Tfh-associated immune response during influenza virus infection in mice. These protocols include: intranasal inoculation of influenza virus; flow cytometry staining and analysis of polyclonal and antigen-specific Tfh cells, GC B cells and plasma cells; immunofluorescence detection of GCs; enzyme-linked immunosorbent assay (ELISA) of influenza virus-specific antibody in serum. These assays basically quantify the differentiation and function of Tfh cells in influenza virus infection, thus providing help for studies in elucidating differentiation mechanism and manipulation strategy.


Assuntos
Centro Germinativo/imunologia , Vírus da Influenza A/imunologia , Infecções por Orthomyxoviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Linfócitos B/imunologia , Linfócitos B/virologia , Centro Germinativo/virologia , Camundongos , Subpopulações de Linfócitos T/virologia , Linfócitos T Auxiliares-Indutores/virologia
19.
Proc Natl Acad Sci U S A ; 117(32): 19408-19414, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719138

RESUMO

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1ß, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia
20.
Ann Hematol ; 99(10): 2315-2322, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32728937

RESUMO

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by lower platelet count resulting from immune cells-mediated platelet clearance. Tacrolimus is an immunosuppressive agent which selectively inhibits T cell activation. Whether tacrolimus plays a role in ITP remains unclear. This study aimed to investigate the effect of tacrolimus on ITP in mice. An ITP mouse model was established by injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin and treated with tacrolimus followed by isolation of peripheral blood mononuclear cells and plasma. The mRNA expression of T-bet, GATA3, and Foxp3 was measured by RT-PCR, and level of IFN-γ, IL-12p70, IL-4, IL-13, and TGF-ß in plasma was measured by ELISA. Tacrolimus inhibited antiplatelet antibody-mediated platelet clearance in ITP mouse model. Meanwhile, tacrolimus-treated ITP mice displayed a significant decrease in the mRNA expression of T-bet and plasma level of IFN-γ and IL-12p70 compared with ITP mice but without differences when compared with normal mice. Furthermore, the expression of GATA3, Foxp3, and plasma level of IL-4 and TGF-ß were upregulated in tacrolimus-treated ITP mice without significant differences to normal mice (except TGF-ß). Tacrolimus prevents antiplatelet antibody-mediated thrombocytopenia in ITP mice possibly through regulating T cell differentiations, suggesting it might be a novel approach for preventing ITP.


Assuntos
Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Tacrolimo/uso terapêutico , Animais , Plaquetas/imunologia , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Isoanticorpos/sangue , Camundongos , Camundongos Endogâmicos C57BL , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Organismos Livres de Patógenos Específicos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
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