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1.
Nat Commun ; 11(1): 5086, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033248

RESUMO

Coronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/patogenicidade , Betacoronavirus/fisiologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interferons/metabolismo , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Carga Viral
2.
Front Immunol ; 11: 559113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072098

RESUMO

As the recent outbreak of SARS-CoV-2 has highlighted, the threat of a pandemic event from zoonotic viruses, such as the deadly influenza A/H7N9 virus subtype, continues to be a major global health concern. H7N9 virus strains appear to exhibit greater disease severity in mammalian hosts compared to natural avian hosts, though the exact mechanisms underlying this are somewhat unclear. Knowledge of the H7N9 host-pathogen interactions have mainly been constrained to natural sporadic human infections. To elucidate the cellular immune mechanisms associated with disease severity and progression, we used a ferret model to closely resemble disease outcomes in humans following influenza virus infection. Intriguingly, we observed variable disease outcomes when ferrets were inoculated with the A/Anhui/1/2013 (H7N9) strain. We observed relatively reduced antigen-presenting cell activation in lymphoid tissues which may be correlative with increased disease severity. Additionally, depletions in CD8+ T cells were not apparent in sick animals. This study provides further insight into the ways that lymphocytes maturate and traffic in response to H7N9 infection in the ferret model.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Infecções por Orthomyxoviridae/imunologia , Animais , Células Apresentadoras de Antígenos/patologia , Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Coronavirus/imunologia , Modelos Animais de Doenças , Furões , Humanos , Infecções por Orthomyxoviridae/patologia , Pandemias , Pneumonia Viral/imunologia
3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1480-1485, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067941

RESUMO

OBJECTIVE: To investigate the correlation of NK cell receptor-interacting serine/threonine kinase 1(RIPK1) activity and expression with prognosis of acute myeloid leukemia (AML) patients with FLT3-ITD mutation. METHODS: A total of 132 AML patients with FLT3-ITD mutation and 136 AML patients with FLT3-WT were selected. Clinical data and the number, length and rearrangement ratio of FLT3-ITD mutations were collected. The ratio of CD4+ T cells, regulatory T cells(Tregs), CD8+ T cells, B cells, natural killer cells(NK cells) and macrophage in peripheral blood(PB) were analyzed by flow cytometry. Correlation of NK cell ratio with FLT3-ITD mutation number, length and rearrangement ratio was analyzed by Pearson correlation analysis. Western blot and RT-qPCR were used to detect RIPK1 protein and mRNA levels in NK cells, respectively. Plasma RIPK activity was detected by ELISA, and Pearson corre-lation analysis was performed for the correlation of RIPK with FLT3-ITD mutation number, length and rearrangement ratio. Kaplan-Meier curve was used to analyze the survival rate of AML patients with FLT3-ITD mutation. RESULTS: Compared with AML patients with FLT3-WT, the white blood cell count in patients with FLT3-ITD mutation significantly increased, PB and BM blasts significantly decreased. There was no significant change in PB CD3+ T cells, Tregs, CD8+ T cells, B cells, M1 and M2 type macrophage of AML patients with FLT3-WT and FLT3-ITD mutation;Compared with AML patients with FLT3-WT, CD4+ T cells significantly decreased, NK cells significantly increased in AML patients wtih FLT3-ITD mutation. NK cells ratio in AML patients with FLT3-ITD mutation significantly positively correlated with the number of FLT3-ITD mutations and rearrangement bases. Plasma RIPK1 activity, RIPK1 protein and mRNA levels in NK cells of AML patients with FLT3-ITD were significantly lower than those of AML patients with FLT3-WT, and negatively correlated with the number of FLT3-ITD mutations, the length of rearranged bases (≥52 bp) and the ratio of rearranged bases. The survival rate of AML patients with FLT3-ITD mutation in low RIPK1 activity after Rydapt treatment was significantly higher than that in high RIPK1 activity. CONCLUSION: The prognosis of AML patients with FLT3-ITD mutation closely relates with plasma RIPK1 activity and RIPK1 expression in NK cells.


Assuntos
Linfócitos T CD8-Positivos , Leucemia Mieloide Aguda , Humanos , Células Matadoras Naturais , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Proteína Serina-Treonina Quinases de Interação com Receptores , Tirosina Quinase 3 Semelhante a fms/genética
4.
Proc Natl Acad Sci U S A ; 117(39): 24384-24391, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32913053

RESUMO

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.


Assuntos
Betacoronavirus/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Antígeno HLA-A2/imunologia , Pneumonia Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T , Feminino , Humanos , Memória Imunológica , Imunofenotipagem , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Pandemias , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Proteínas Virais/química , Proteínas Virais/imunologia
5.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(6): 856-863, 2020 Jun 30.
Artigo em Chinês | MEDLINE | ID: mdl-32895201

RESUMO

OBJECTIVE: To investigate whether interleukin-12 (IL-12) over-expression in malignant melanoma B16 cells affects the expression level of programmed death-1 (PD-1) on T cells in mice during immune microenvironment reconstruction. METHODS: B16 cells were transfected with an IL-12 expression lentiviral vector, and IL-12 over-expression in the cells was verified qPCR and ELISA. Plate cloning assay was used to compare the cell proliferation activity between B16 cells and B16/IL-12 cells. The expression of IL-12 protein in B16/IL-12 cells-derived tumor tissue were detected by ELISA. C57BL/6 mice were inoculated with B16 cells or B16/IL-12 cells, and 14 days later the proportion of T cells with high expression of PD-1 in the tumor-draining lymph nodes was detected by flow cytometry. Mouse models of immune reconstitution established by 650 cGy X-ray radiation were inoculated with B16 (B16+RT group) or B16/IL-12 (B16/IL-12+RT group) cells, with the mice without X-ray radiation prior to B16 cell inoculation as controls. Tumor growth in the mice was recorded at different time points, and on day 14, flow cytometry was performed to detect the proportion of T cells with high PD-1 expression in the tumor-draining lymph nodes and in the tumor tissue. RESULTS: B16 cells infected with the IL-12-overexpressing lentiviral vector showed significantly increased mRNA and protein levels of IL-12 (P < 0.001) without obvious changes in cell viability (P>0.05). B16/IL-12 cells expressed higher levels of IL-12 than B16 cells in vivo (P < 0.01). In the tumor-bearing mouse models, the proportion of CD4 + PD-1+ T cells was significantly lower in B16/IL-12 group than in B16 group (P < 0.01). In the mice with X-ray radiation-induced immune reconstitution, PD-1 expressions on CD4+ T cells (P < 0.05) and CD8+ T cells (P < 0.01) were significantly higher in B16+ RT group than in the control mice and in B16/IL-12+RT group (P < 0.01 or 0.001); the tumors grew more slowly in B16/IL-12+RT group than in B16 + RT group (P < 0.001). CONCLUSIONS: During immune microenvironment reconstruction, overexpression IL-12 in the tumor microenvironment can reduce the percentage of PD-1 + T cells and suppress the growth of malignant melanoma in mice.


Assuntos
Reconstituição Imune , Melanoma Experimental , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Interleucina-12 , Camundongos , Camundongos Endogâmicos C57BL , Microambiente Tumoral
6.
Medicine (Baltimore) ; 99(36): e20993, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32898991

RESUMO

Radiotherapy (RT) can affect the immune function of patients with cancer. The purpose of this study was to investigate the effect of RT on lymphocyte and its subsets in patients with esophageal cancer (EC).All patients received RT with a mean dose of 5369 cGy (gray). Blood parameters were measured in 31 patients on 3 occasions (before, at the end of radiotherapy, and at 3 months follow-up). The whole blood count and lymphocyte subsets were measured and correlated with short time efficiency and radiation dose parameters.White blood count (WBC) and lymphocyte count (ALC) were greatly decreased at the end of radiotherapy, and the percentages of CD3+, CD3+CD8+ T cells were significantly increased, on the other hand, a decrease in the CD4/CD8 ratio was observed. The percentages of CD3-CD16/56+NK cells and CD19+ B cell were decreased at the end of RT compared with prior RT. The percentages of CD3+ T cells before RT and the WBC and ALC count after RT can be used as prognostic indicators for survival. The PTV dose can cause significant changes in lymphocytes count after RT. CD3+T cells after RT were significantly correlated with mean heart dose and heart V50.Our study identified that RT causes changes in lymphocyte subsets, and these changes may indicate differences in immune function between individuals. Radiotherapy plan should be designed to minimize normal tissue dose to reduce the impact on WBC and lymphocytes.


Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/radioterapia , Subpopulações de Linfócitos/imunologia , Idoso , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Estudos Retrospectivos
7.
Nat Commun ; 11(1): 4454, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901001

RESUMO

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/virologia , Doença Crônica , Citotoxicidade Imunológica , Modelos Animais de Doenças , Regulação para Baixo , Tolerância Imunológica , Imunidade Celular , Técnicas In Vitro , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Transdução de Sinais/imunologia
8.
Nat Commun ; 11(1): 4475, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901029

RESUMO

Tissue resident memory CD8+ T cells (Trm) are poised for immediate reactivation at sites of pathogen entry and provide optimal protection of mucosal surfaces. The intestinal tract represents a portal of entry for many infectious agents; however, to date specific strategies to enhance Trm responses at this site are lacking. Here, we present TMDI (Transient Microbiota Depletion-boosted Immunization), an approach that leverages antibiotic treatment to temporarily restrain microbiota-mediated colonization resistance, and favor intestinal expansion to high densities of an orally-delivered Listeria monocytogenes strain carrying an antigen of choice. By augmenting the local chemotactic gradient as well as the antigenic load, this procedure generates a highly expanded pool of functional, antigen-specific intestinal Trm, ultimately enhancing protection against infectious re-challenge in mice. We propose that TMDI is a useful model to dissect the requirements for optimal Trm responses in the intestine, and also a potential platform to devise novel mucosal vaccination approaches.


Assuntos
Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas , Administração Oral , Animais , Antígenos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade nas Mucosas/efeitos dos fármacos , Memória Imunológica , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem , Estreptomicina/administração & dosagem
9.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917858

RESUMO

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral/transplante , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
10.
Medicine (Baltimore) ; 99(37): e22170, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925784

RESUMO

BACKGROUND: Evidence suggests that metastasis is chiefly responsible for the poor prognosis of colon adenocarcinoma (COAD). The tumor microenvironment plays a vital role in regulating this biological process. However, the mechanisms involved remain unclear. The aim of this study was to identify crucial metastasis-related biomarkers in the tumor microenvironment and investigate its association with tumor-infiltrating immune cells. METHODS: We obtained gene expression profiles and clinical information from The Cancer Genome Atlas database. According to the "Estimation of STromal and Immune cells in MAlignant Tumor tissue using Expression data" algorithm, each sample generated the immune and stromal scores. Following correlation analysis, the metastasis-related gene was identified in The Cancer Genome Atlas database and validated in the GSE40967 dataset from Gene Expression Omnibus. The correlation between metastasis-related gene and infiltrating immune cells was assessed using the Tumor IMmune Estimation Resource database. RESULTS: The analysis included 332 patients; the metastatic COAD samples showed a low immune score. Correlation analysis results showed that interferon regulatory factor 1 (IRF1) was associated with tumor stage, lymph node metastasis, and distant metastasis. Furthermore, significant associations between IRF1 and CD8+ T cells, T cell (general), dendritic cells, T-helper 1 cells, and T cell exhaustion were demonstrated by Spearmans correlation coefficients and P values. CONCLUSIONS: The present findings suggest that IRF1 is associated with metastasis and the degree of immune infiltration of CD8+ T cells (general), dendritic cells, T-helper 1 cells, and T cell exhaustion in COAD. These results may provide information for immunotherapy in colon cancer.


Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Fator Regulador 1 de Interferon/imunologia , Linfócitos T/imunologia , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/metabolismo , Bases de Dados Genéticas , Células Dendríticas/metabolismo , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/imunologia , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral
11.
BMC Infect Dis ; 20(1): 677, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32942991

RESUMO

BACKGROUND: Approximately 80% - 90% of individuals infected with latent Mycobacterium tuberculosis (Mtb) remain protected throughout their life-span. The release of unique, latent-phase antigens are known to have a protective role in the immune response against Mtb. Although the BCG vaccine has been administered for nine decades to provide immunity against Mtb, the number of TB cases continues to rise, thereby raising doubts on BCG vaccine efficacy. The shortcomings of BCG have been associated with inadequate processing and presentation of its antigens, an inability to optimally activate T cells against Mtb, and generation of regulatory T cells. Furthermore, BCG vaccination lacks the ability to eliminate latent Mtb infection. With these facts in mind, we selected six immunodominant CD4 and CD8 T cell epitopes of Mtb expressed during latent, acute, and chronic stages of infection and engineered a multi-epitope-based DNA vaccine (C6). RESULT: BALB/c mice vaccinated with the C6 construct along with a BCG vaccine exhibited an expansion of both CD4 and CD8 T cell memory populations and augmented IFN-γ and TNF-α cytokine release. Furthermore, enhancement of dendritic cell and macrophage activation was noted. Consequently, illustrating the elicitation of immunity that helps in the protection against Mtb infection; which was evident by a significant reduction in the Mtb burden in the lungs and spleen of C6 + BCG administered animals. CONCLUSION: Overall, the results suggest that a C6 + BCG vaccination approach may serve as an effective vaccination strategy in future attempts to control TB.


Assuntos
Vacina BCG/imunologia , Epitopos de Linfócito T , Tuberculose/prevenção & controle , Vacinas de DNA/imunologia , Animais , Antígenos de Bactérias/imunologia , Vacina BCG/genética , Vacina BCG/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/genética , Feminino , Memória Imunológica , Interferon gama/metabolismo , Tuberculose Latente/prevenção & controle , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinas de DNA/farmacologia
12.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Int Med Res ; 48(9): 300060520958594, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32962495

RESUMO

OBJECTIVE: Coronavirus disease 2019 (COVID-19) shows a wide range of severity, ranging from an asymptomatic presentation to a severe illness requiring intensive care unit admission. Identification of a strategy to manage the severity of this disease will not only help to reduce its case fatality but also help to remove some of the burden from the already overwhelmed health care systems. While successful management of symptoms in general is important, identifying measures to modify the severity of the illness is a key factor in the fight against this pandemic. METHODS: This paper presents a short literature review to suggest a new treatment modality for COVID-19. RESULTS: COVID-19 is less severe and rarely fatal in children than in adults, which could be caused by greater fluctuations of plasma epinephrine in children. Our literature survey endorses this hypothesis according to both the epidemiological and immunological findings. CONCLUSION: Application of epinephrine pulses with a specific amplitude may be considered an intervention to minimize the severity of COVID-19.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Epinefrina/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Adulto , Fatores Etários , Doenças Assintomáticas , Biomarcadores/sangue , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Criança , Ritmo Circadiano/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Esquema de Medicação , Epinefrina/sangue , Epinefrina/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Modelos Imunológicos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Prognóstico , Índice de Gravidade de Doença
14.
PLoS Pathog ; 16(9): e1008827, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32886721

RESUMO

Global burden of cervical cancer, the most common cause of mortality caused by human papillomavirus (HPV), is expected to increase during the next decade, mainly because current alternatives for HPV vaccination and cervical cancer screening programs are costly to be established in low-and-middle income countries. Recently, we described the development of the broadly protective, thermostable vaccine antigen Trx-8mer-OVX313 based on the insertion of eight different minor capsid protein L2 neutralization epitopes into a thioredoxin scaffold from the hyperthermophilic archaeon Pyrococcus furiosus and conversion of the resulting antigen into a nanoparticle format (median radius ~9 nm) upon fusion with the heptamerizing OVX313 module. Here we evaluated whether the engineered thioredoxin scaffold, in addition to humoral immune responses, can induce CD8+ T-cell responses upon incorporation of MHC-I-restricted epitopes. By systematically examining the contribution of individual antigen modules, we demonstrated that B-cell and T-cell epitopes can be combined into a single antigen construct without compromising either immunogenicity. While CD8+ T-cell epitopes had no influence on B-cell responses, the L2 polytope (8mer) and OVX313-mediated heptamerization of the final antigen significantly increased CD8+ T-cell responses. In a proof-of-concept experiment, we found that vaccinated mice remained tumor-free even after two consecutive tumor challenges, while unvaccinated mice developed tumors. A cost-effective, broadly protective vaccine with both prophylactic and therapeutic properties represents a promising option to overcome the challenges associated with prevention and treatment of HPV-caused diseases.


Assuntos
Antígenos de Neoplasias , Antígenos Virais , Proteínas Arqueais , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer , Imunidade Celular/efeitos dos fármacos , Nanopartículas , Papillomaviridae , Vacinas contra Papillomavirus , Pyrococcus furiosus/química , Tiorredoxinas , Neoplasias do Colo do Útero/imunologia , Animais , Antígenos de Neoplasias/química , Antígenos de Neoplasias/farmacologia , Antígenos Virais/química , Antígenos Virais/farmacologia , Proteínas Arqueais/química , Proteínas Arqueais/farmacologia , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/química , Vacinas Anticâncer/farmacologia , Epitopos de Linfócito B/química , Epitopos de Linfócito B/farmacologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Papillomaviridae/química , Papillomaviridae/imunologia , Vacinas contra Papillomavirus/química , Vacinas contra Papillomavirus/farmacologia , Tiorredoxinas/química , Tiorredoxinas/farmacologia , Neoplasias do Colo do Útero/virologia
15.
Lancet ; 396(10254): 839-852, 2020 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-32888407

RESUMO

BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Idoso , Idoso de 80 Anos ou mais , Anemia/epidemiologia , Antígenos CD19/administração & dosagem , Antígenos CD19/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Síndrome da Liberação de Citocina/epidemiologia , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese/métodos , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Doenças do Sistema Nervoso/epidemiologia , Neutropenia/epidemiologia , Recidiva , Segurança , Análise de Sobrevida , Trombocitopenia/epidemiologia , Resultado do Tratamento
16.
Nat Commun ; 11(1): 4520, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908154

RESUMO

Tumor extracellular matrix has been associated with drug resistance and immune suppression. Here, proteomic and RNA profiling reveal increased collagen levels in lung tumors resistant to PD-1/PD-L1 blockade. Additionally, elevated collagen correlates with decreased total CD8+ T cells and increased exhausted CD8+ T cell subpopulations in murine and human lung tumors. Collagen-induced T cell exhaustion occurs through the receptor LAIR1, which is upregulated following CD18 interaction with collagen, and induces T cell exhaustion through SHP-1. Reduction in tumor collagen deposition through LOXL2 suppression increases T cell infiltration, diminishes exhausted T cells, and abrogates resistance to anti-PD-L1. Abrogating LAIR1 immunosuppression through LAIR2 overexpression or SHP-1 inhibition sensitizes resistant lung tumors to anti-PD-1. Clinically, increased collagen, LAIR1, and TIM-3 expression in melanoma patients treated with PD-1 blockade predict poorer survival and response. Our study identifies collagen and LAIR1 as potential markers for immunotherapy resistance and validates multiple promising therapeutic combinations.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Colágeno/metabolismo , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Imunológicos/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Transgênicos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Receptores Imunológicos/genética
18.
Zhonghua Yi Xue Za Zhi ; 100(34): 2669-2674, 2020 Sep 15.
Artigo em Chinês | MEDLINE | ID: mdl-32921015

RESUMO

Objective: To investigate Notch receptor expression in CD8(+) T cells in patients with prostate cancer, and to assess the influence of Notch signaling pathway on the function of CD8(+)T cells inpatients with prostate cancer. Methods: Forty-five patients with prostate cancer, forty-one patients with nonbacterial prostatitis, and thirty healthy controls who were hospitalized or followed-up in Shanxi Provincial People's Hospital between November 2017 and June 2018 were enrolled. CD8(+)T cells were purified, and mRNA relative levels of Notch1-4 were semi-quantified by reverse transcriptional real-time PCR. CD8(+)T cells were stimulated with Notch signaling inhibitor γ-secretase inhibitor (GSI). mRNA relative levels of perforin, granzyme B, and FasL were semi-quantified by reverse transcriptional real-time PCR. Percentages of PD-1 and CTLA-4 positive cells were investigated by flow cytometry. Direct contact and indirect contact coculture systems were set up between CD8(+)T cells and prostate cancer cell line LAPC4 cells. The influence of Notch signaling inhibition to CD8(+)T cell cytotoxicitywas assessed by measuringtarget cell death and cytokine secretion. One-Way ANOVA, LSD-t test, and paired t test was used for comparison. Results: mRNA relative levels of Notch1~4 were elevated in CD8(+)T cells from prostate cancer patients when compared with those from healthy controls and nonbacterial prostatitis patients (all P<0.05). There was CD8(+)T cell exhaustion in prostate cancer patients, which presented as decreased mRNA relative levels of perforin, granzyme B, and FasL (all P<0.000 1), as well as increased percentage of PD-1(+)CD8(+) (19.3%±5.4%) and CTLA-4(+)CD8(+)(11.7%±3.9%) cells. CD8(+)T cells from prostate cancer patients induced LAPC cell death was downregulated in direct contact coculture system (28.8%±6.4% vs 37.2%±2.6%, P=0.015). IFN-γsecretion was also reduced ((61.7±10.6)ng/L vs (88.6±20.2)ng/L, P=0.003 2). Inhibition of Notch signaling by GSI increased mRNA of perforin, granzyme B, and FasL in CD8(+)T cells from prostate cancer patients (all P<0.01), while reduced percentage of PD-1(+)CD8(+)(12.6%±2.5% vs 17.4%±4.7%, P=0.005 9) and CTLA-4(+)CD8(+) (12.0%±1.0% vs 14.1%±3.1%, P=0.011)cells. Notch signaling inhibition promoted LAPC4 cell death (34.3%±7.2%, P=0.000 2) which induced by prostate cancer derived CD8(+)T cells, and increased IFN-γ production ((88.4±33.6)ng/L, P=0.008 3). Conclusion: Elevated Notch receptors induced CD8(+)T cells exhaustion in prostate cancer patients.


Assuntos
Neoplasias da Próstata , Receptores Notch , Linfócitos T CD8-Positivos , Humanos , Masculino , Perforina , Transdução de Sinais
19.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
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