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1.
Urol Clin North Am ; 47(4): 433-442, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33008494

RESUMO

Natural killer (NK) cells are potently cytolytic innate lymphocytes involved in the immune surveillance of tumors and virally infected cells. Although much progress has been made in manipulating the ability of T cells to recognize and eliminate tumors, a comprehensive understanding of NK-cell infiltration into solid tumors, and their amenability to immunomodulation, remains incomplete. This article discusses recent studies showing that urologic tumors are infiltrated by NK cells and that these NK cells are often dysfunctional, but that strategies interfering with inhibitory axes have significant potential to alleviate this dysfunction.


Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias Urogenitais/terapia , Terapia Biológica/métodos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Masculino , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/terapia , Medição de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Neoplasias Urogenitais/imunologia
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
4.
Sci Rep ; 10(1): 15838, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985562

RESUMO

The coronavirus disease 2019 (COVID-19) has been spreading worldwide. Severe cases quickly progressed with unfavorable outcomes. We aim to investigate the clinical features of COVID-19 and identify the risk factors associated with its progression. Data of confirmed SARS-CoV-2-infected patients and healthy participants were collected. Thirty-seven healthy people and 79 confirmed patients, which include 48 severe patients and 31 mild patients, were recruited. COVID-19 patients presented with dysregulated immune response (decreased T, B, and NK cells and increased inflammatory cytokines). Also, they were found to have increased levels of white blood cell, neutrophil count, and D-dimer in severe cases. Moreover, lymphocyte, CD4+ T cell, CD8+ T cell, NK cell, and B cell counts were lower in the severe group. Multivariate logistic regression analysis showed that CD4+ cell count, neutrophil-to-lymphocyte ratio (NLR) and D-dimer were risk factors for severe cases. Both CT score and clinical pulmonary infection score (CPIS) were associated with disease severity. The receiver operating characteristic (ROC) curve analysis has shown that all these parameters and scores had quite a high predictive value. Immune dysfunction plays critical roles in disease progression. Early and constant surveillance of complete blood cell count, T lymphocyte subsets, coagulation function, CT scan and CPIS was recommended for early screening of severe cases.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Fenômenos do Sistema Imunológico/fisiologia , Pneumonia Viral/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/patologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
5.
Anticancer Res ; 40(10): 5687-5700, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988894

RESUMO

BACKGROUND: We previously developed a novel technique for expanding highly activated and purified natural killer (NK) cells able to maximize the theoretical activation potential of NK cells; thus, we named this cell population zenithal-NK (ZNK). AIM: To evaluate the safety, feasibility, and preliminary efficacy of autologous ZNK cells in patients with different types of advanced cancer with measurable solid lesions. PATIENTS AND METHODS: In this phase I/IIb first-in-human, open-label, dose-escalation study (trial registration ID: UMIN-000011555), eligible patients received ZNK cells intravenously starting from 106 to 108 cells/patient/dose at 2-week dosing intervals. A maximum of six cycles were allowed. Safety and survival analyses were also carried out for cases that were excluded and never administered ZNK cells. RESULTS: As of April 20, 2017, a total of nine patients were enrolled in this study, with one recruited twice. Overall, neither grade 2 or higher toxicities (Common Terminology Criteria for Adverse Events v5.0) caused by cell administration, nor adverse events causing discontinuation of protocol treatment were found. In four cases, the number of administered ZNK cells was increased to 108 cells/body/dose without any serious dose-limiting toxicity; the maximally tolerated dose was therefore considered to be at least 108 cells. The overall response rate was 40.0% in 10 net cases, one of partial response and three of stable disease, and the patient with partial response is still alive after 4 year's observation. CONCLUSION: These results demonstrate that autologous ZNK cells are safe and well-tolerated in patients with different types of advanced solid tumors. Clinical studies using similarly active ZNK cells from human leukocyte antigen/killer cell immunoglobulin-like receptor-mismatched healthy donors under Good Manufacturing Practice-compliant manufacturing, and with modified treatment regimen, i.e. doses and frequencies, are warranted for further investigation to show the potential of ZNK cells in such patients.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Células Matadoras Naturais/transplante , Neoplasias/terapia , Transplante Autólogo/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Relação Dose-Resposta Imunológica , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia
6.
Front Immunol ; 11: 1942, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983123

RESUMO

Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1ß is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CD56/metabolismo , Infecções por Coronavirus/virologia , Evolução Fatal , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/sangue , Células Matadoras Naturais/imunologia , Masculino , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Índice de Gravidade de Doença
7.
Nat Commun ; 11(1): 4387, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873795

RESUMO

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell tri-cell co-culture system, neutrophils are shown to potentially suppress the tumoricidal activity of NK cells, while neutrophils themselves are tumoricidal. Intriguingly, these two modulatory effects by neutrophils are both mediated by reactive oxygen species. Collectively, the absence or presence of NK cells, governs the net tumor-modulatory effects of neutrophils.


Assuntos
Células Matadoras Naturais/imunologia , Neoplasias Pulmonares/imunologia , Neoplasias Mamárias Animais/imunologia , Neutropenia/prevenção & controle , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral/transplante , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/sangue , Neoplasias Mamárias Animais/complicações , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos NOD , Neutropenia/sangue , Neutropenia/etiologia , Neutropenia/imunologia , Neutrófilos/efeitos dos fármacos , Cultura Primária de Células
8.
Int J Mol Sci ; 21(17)2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32883007

RESUMO

When facing an acute viral infection, our immune systems need to function with finite precision to enable the elimination of the pathogen, whilst protecting our bodies from immune-related damage. In many instances however this "perfect balance" is not achieved, factors such as ageing, cancer, autoimmunity and cardiovascular disease all skew the immune response which is then further distorted by viral infection. In SARS-CoV-2, although the vast majority of COVID-19 cases are mild, as of 24 August 2020, over 800,000 people have died, many from the severe inflammatory cytokine release resulting in extreme clinical manifestations such as acute respiratory distress syndrome (ARDS) and hemophagocytic lymphohistiocytosis (HLH). Severe complications are more common in elderly patients and patients with cardiovascular diseases. Natural killer (NK) cells play a critical role in modulating the immune response and in both of these patient groups, NK cell effector functions are blunted. Preliminary studies in COVID-19 patients with severe disease suggests a reduction in NK cell number and function, resulting in decreased clearance of infected and activated cells, and unchecked elevation of tissue-damaging inflammation markers. SARS-CoV-2 infection skews the immune response towards an overwhelmingly inflammatory phenotype. Restoration of NK cell effector functions has the potential to correct the delicate immune balance required to effectively overcome SARS-CoV-2 infection.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Autoimunidade , Infecções por Coronavirus/metabolismo , Humanos , Imunomodulação , Células Matadoras Naturais/metabolismo , Pandemias , Pneumonia Viral/metabolismo
9.
PLoS Pathog ; 16(8): e1008820, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32845937

RESUMO

The COVID-19 pandemic has caused more than 575,000 deaths worldwide as of mid-July 2020 and still continues globally unabated. Immune dysfunction and cytokine storm complicate the disease, which in turn leads to the question of whether stimulation or suppression of the immune system would curb the disease. Given the varied antiviral and regulatory functions of natural killer (NK) cells, they could be potent and powerful immune allies in this global fight against COVID-19. Unfortunately, there is somewhat limited knowledge of the role of NK cells in SARS-CoV-2 infections and even in the related SARS-CoV-1 and MERS-CoV infections. Several NK cell therapeutic options already exist in the treatment of tumor and other viral diseases and could be repurposed against COVID-19. In this review, we describe the current understanding and potential roles of NK cells and other Fc receptor (FcR) effector cells in SARS-CoV-2 infection, advantages of using animals to model COVID-19, and NK cell-based therapeutics that are being investigated for COVID-19 therapy.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Células Matadoras Naturais/imunologia , Pneumonia Viral/imunologia , Animais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia
10.
Sci Immunol ; 5(50)2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32826343

RESUMO

Understanding innate immune responses in COVID-19 is important to decipher mechanisms of host responses and interpret disease pathogenesis. Natural killer (NK) cells are innate effector lymphocytes that respond to acute viral infections but might also contribute to immunopathology. Using 28-color flow cytometry, we here reveal strong NK cell activation across distinct subsets in peripheral blood of COVID-19 patients. This pattern was mirrored in scRNA-seq signatures of NK cells in bronchoalveolar lavage from COVID-19 patients. Unsupervised high-dimensional analysis of peripheral blood NK cells furthermore identified distinct NK cell immunotypes that were linked to disease severity. Hallmarks of these immunotypes were high expression of perforin, NKG2C, and Ksp37, reflecting increased presence of adaptive NK cells in circulation of patients with severe disease. Finally, arming of CD56bright NK cells was observed across COVID-19 disease states, driven by a defined protein-protein interaction network of inflammatory soluble factors. This study provides a detailed map of the NK cell activation landscape in COVID-19 disease.


Assuntos
Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Células Matadoras Naturais/imunologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Índice de Gravidade de Doença , Imunidade Adaptativa , Antígeno CD56/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/patologia , Feminino , Citometria de Fluxo/métodos , Humanos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Fenótipo , Pneumonia Viral/sangue , Pneumonia Viral/patologia , Reação em Cadeia da Polimerase , Estudos Prospectivos , Mapas de Interação de Proteínas/imunologia , Receptores KIR/metabolismo , Testes Sorológicos , Suécia/epidemiologia
11.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788748

RESUMO

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Pneumonia Viral/imunologia , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , RNA-Seq , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Índice de Gravidade de Doença , Análise de Célula Única
12.
Adv Biol Regul ; 77: 100737, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773100

RESUMO

Natural killer (NK) cells are pivotal effectors of the innate immunity protecting an individual from microbes. They are the first line of defense against invading viruses, given their substantial ability to directly target infected cells without the need for specific antigen presentation. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify and modulate antiviral adaptive immune responses. In this review, we will examine the role of NK cells in SARS-COV2 infections causing the ongoing COVID19 pandemic, keeping in mind the controversial role of NK cells specifically in viral respiratory infections and in inflammatory-driven lung damage. We discuss lessons learnt from previous coronavirus outbreaks in humans (caused by SARS-CoV-1 and MERS-COV).


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Células Matadoras Naturais/imunologia , Pandemias , Pneumonia Viral/epidemiologia , Insuficiência Respiratória/epidemiologia , Doença Aguda , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucinas/genética , Interleucinas/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/virologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Ativação Linfocitária , Proteína 1 de Membrana Associada ao Lisossomo/genética , Proteína 1 de Membrana Associada ao Lisossomo/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1167-1170, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798393

RESUMO

OBJECTIVE: To investigate the effect of chidamide on the killing activity of NK (Natural killer cell, NK) cells targeting K562 cells and its related mechanism. METHODS: K562 cells were pretreated with chidamide at different concentrations and cocultured with NK cells at different effect-target ratios. The killing effect of chidamide on K562 cells by NK cells, the expression of natural killer group 2 member D (NKG2D) ligands and apoptosis rate of K562 cells were detected by flow cytometry. RESULTS: The killing sensitivity of NK cells to K562 cells could be enhanced by chidamide. The expression of ULBP2 on K562 cell surface could be up-regulate, however, the expression of ULBP1 and MICA/MICB showed no statistically difference as compared with control group. Chidamide showed no obvious cytotoxicity to K562 cells. CONCLUSION: Chidamide can significantly improve killing efficiency of NK cells on K562 cells, which may be related to the up-regulation of ULBP2 expression.


Assuntos
Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais/imunologia , Aminopiridinas , Benzamidas , Proteínas Ligadas por GPI , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células K562 , Subfamília K de Receptores Semelhantes a Lectina de Células NK
14.
Science ; 369(6506): 993-999, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820126

RESUMO

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.


Assuntos
Antineoplásicos/farmacologia , Materiais Biomiméticos/farmacologia , Proteínas de Membrana/metabolismo , Nucleotídeos Cíclicos/farmacologia , Animais , Antígeno B7-H1/metabolismo , Materiais Biomiméticos/química , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Cristalografia por Raios X , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Camundongos , Nucleotídeos Cíclicos/química , Conformação Proteica/efeitos dos fármacos
15.
Cells ; 9(9)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859121

RESUMO

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells' exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.


Assuntos
Betacoronavirus/química , Infecções por Coronavirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Doadores de Sangue , Brônquios/citologia , Degranulação Celular/genética , Técnicas de Cocultura , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Células Epiteliais/metabolismo , Humanos , Interferon gama/metabolismo , Células K562 , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , RNA Viral/genética , Vírus da SARS/química , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Transfecção
16.
Mult Scler ; 26(10): 1261-1264, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32762494

RESUMO

Approximately 200,000 multiple sclerosis (MS) patients worldwide receive B-cell-depleting immunotherapy with rituximab (anti-CD20), which eliminates the ability to generate an antibody response to new infections. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies might help viral clearance, these patients could be at risk of severe complications if infected. Here, we report on an MS patient who had received rituximab for ~3 years. The patient was examined 5 days before the onset of coronavirus disease 2019 (COVID-19) symptoms and was admitted to the hospital 2 days after. She recovered 14 days after symptom onset despite having a 0% B lymphocyte count and not developing SARS-CoV-2 immunoglobulin G (IgG) antibodies.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por Coronavirus/imunologia , Imunidade Celular/imunologia , Células Matadoras Naturais/imunologia , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Pneumonia Viral/imunologia , Rituximab/uso terapêutico , Betacoronavirus , Relação CD4-CD8 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Progressão da Doença , Feminino , Humanos , Contagem de Linfócitos , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia
18.
Transplantation ; 104(8): 1574-1579, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732834

RESUMO

BACKGROUND: Antibody-dependent cell-mediated cytotoxicity (ADCC) is an important pathway responsible for antibody-mediated rejection (AMR). Imlifidase (IdeS) cleaves human IgG into F(ab')2 and Fc fragments, potentially inhibiting ADCC. Here we examined the effect of IdeS on allo-antibody-mediated NK cell activation (Allo-CFC) and ADCC in vitro. METHODS: For Allo-CFC, normal whole blood was incubated with third-party peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody positive (HS) or negative (NC) sera to measure IFNγ+ NK cell%. For ADCC, normal PBMCs were incubated with Farage B (FB) cells with HS or NC sera to measure 7-AAD+ lysed FB cell%. To assess the effect of IdeS on these assays, serum-treated PBMCs (Allo-CFC-1) and serum used for PBMC pretreatment (Allo-CFC-2) in Allo-CFC, and serum used for ADCC were preincubated with IdeS. Sera from IdeS-treated patients were also tested for Allo-CFC (Allo-CFC-3). RESULTS: IFNγ+ NK cell% were significantly elevated in HS versus NC sera in Allo-CFC-1 (10 ± 3% versus 2 ± 1%, P = 0.001), Allo-CFC-2 (20 ± 10% versus 4 ± 2%, P = 0.01) and 7AAD+ FB cell% (11 ± 3% versus 4 ± 2%, P = 0.02) in ADCC. These were significantly reduced by IdeS treatment. Patient sera with significantly reduced anti-HLA antibody levels at 1 day postimlifidase lost the capacity to activate NK cells in Allo-CFC-3, but those at 1-3 months postimlifidase regained the capacity. CONCLUSIONS: IdeS inhibited NK cell activation and ADCC in vitro and in treated patients. These results and reported inhibition of complement activating anti-HLA antibodies by IdeS suggest its possible role in treatment of AMR.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Proteínas de Bactérias/uso terapêutico , Imunossupressores/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Transplante de Órgãos/efeitos adversos , Adulto , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Proteínas de Bactérias/farmacologia , Bioensaio , Células Cultivadas , Ativação do Complemento/efeitos dos fármacos , Dessensibilização Imunológica/métodos , Antígenos HLA/imunologia , Humanos , Imunossupressores/uso terapêutico , Interferon gama/imunologia , Interferon gama/metabolismo , Isoanticorpos/imunologia , Isoanticorpos/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares , Cultura Primária de Células , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Transplante Homólogo/efeitos adversos
19.
Front Immunol ; 11: 1692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754162

RESUMO

Coronavirus-induced disease-2019 (COVID-19) continues to cause significant morbidity and mortality worldwide. While studies on SARS-CoV-2 effects on immune cell function continue to progress, we know very little about the significance of depletion of key immune effectors by the virus in the mortality and morbidity of the disease. This commentary outlines what is the reported literature thus far on the effect of virus on NK cells known to kill virally infected cells. It also underscores the necessity for the future comprehensive studies of NK cells in SARS-CoV-2 infected individuals and animal models to better understand the role and significance of reported NK cell depletion and functional inactivation in disease morbidity and mortality, in hope to design effective therapeutic interventions for the disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Adulto , Idoso , Animais , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Citocinas/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia
20.
Crit Rev Immunol ; 40(2): 167-171, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749094

RESUMO

Coronavirus disease 2019 (COVID-19) poses a great public health challenge worldwide. While studies on the effects of SARS-CoV-2 on immune cell function continue to progress, we know very little about the significance of depletion of key immune effectors by the virus in the mortality and morbidity of the disease. This commentary reviews what is known thus far about the effects of the virus on natural killer (NK) cells, the major cell type responsible for the destruction and removal of virally infected cells. It also highlights the necessity of comprehensive studies of NK cells in COVID-19 patients and animal models to better understand the role and significance of reported NK depletion and functional inactivation in disease morbidity and mortality, in the hopes of designing effective therapeutic interventions for the disease.


Assuntos
Infecções por Coronavirus/patologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Pneumonia Viral/patologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Humanos , Interferon gama/imunologia , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Fator de Necrose Tumoral alfa/imunologia
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