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1.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218162

RESUMO

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein 70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intracranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2-treated NK cells as compared to those subjected to nontreated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2-treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Glioblastoma/patologia , Proteínas de Choque Térmico HSP70/farmacologia , Interleucina-2/farmacologia , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Glioblastoma/metabolismo , Imunofenotipagem , Células Matadoras Naturais/imunologia , Masculino , Ratos
2.
BMC Infect Dis ; 20(1): 185, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111171

RESUMO

BACKGROUND: Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis. METHODS: C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage. RESULTS: Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection. CONCLUSIONS: Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model.


Assuntos
Artrite Infecciosa/prevenção & controle , Terapia Genética , Interleucina-2/genética , Staphylococcus aureus/patogenicidade , Animais , Anticorpos Monoclonais/uso terapêutico , Artrite Infecciosa/etiologia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/metabolismo , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/uso terapêutico , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
3.
Zhonghua Xue Ye Xue Za Zhi ; 41(2): 143-148, 2020 Feb 14.
Artigo em Chinês | MEDLINE | ID: mdl-32135632

RESUMO

Objective: To study the value of unmethylated cytosine guanine dinucleotide oligodeoxynucleotide (DSP30) and IL-2 in the conventional cytogenetic (CA) detection of the chromosomal aberrations in chronic lymphocytic leukemia (CLL) . Methods: Bone marrow or peripheral blood cells of CLL patients were cultured with DSP30 plus IL-2 for 72 h, following which R-banding analysis was conducted. Fluorescence in situ hybridization (FISH) was performed in 85 patients. CA results were compared with data obtained by FISH. Results: Among 89 CLL patients, the success rate of chromosome analysis was 94.38% (84/89) . Clonal aberrations were detected in 51 patients (51/84, 60.71%) . Of them, 27 (27/51, 52.94%) were complex karyotype. Among 85 CLL patients tested by FISH, chromosomal abnormalities were detected in 74 (74/85, 87.06%) patients, of which 2 (2/74) patients were complex karyotypes, accounting for 2.70%. Of the 85 CLL patients examined by FISH, 50 had abnormal karyotype analysis, 30 had normal karyotype, 5 failed to have chromosome analysis. Among them, 25 cases showed clonal aberrations by FISH assay but normal by CA, and 4 cases were normal by FISH but displayed aberrations in chromosome analysis, and totally 78 (91.76%) cases with abnormality detected by the combination of the two methods. The frequency of 13q- abnormality detected by FISH was significantly higher than that by CA analysis (69.41%vs 16.67%, P<0.001) , while the frequency of 11q-,+12 and 17p- detected by two methods showed no significant difference (P>0.05) . The detection rate of complex abnormalities in conventional karyotype analysis was higher than that in FISH (50.98%vs 2.70%) . In addition, 11 low-risk and 9 intermediate-risk patients according to FISH results showed complex karyotype by cytogenetics, and were classified into high-risk cytogenetic subgroup. Conclusion: DSP30 and IL-2 are effective in improving the detection rate of CA in CLL patients (60.71%) and CA is more effective to detect complex karyotype. However, FISH had a higher overall abnormality detection rate (87.06%) than CA, especially for 13q-. The combination of CA and FISH not only enhanced the detection rate of clonal aberrations to 91.76%, but also provided more precise prognosis stratification for CLL patients, thus to provide more information for clinical implication.


Assuntos
Leucemia Linfocítica Crônica de Células B , Aberrações Cromossômicas , Citogenética , Humanos , Hibridização in Situ Fluorescente , Interleucina-2
4.
Immunity ; 52(2): 313-327.e7, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32049052

RESUMO

T cell responses upon infection display a remarkably reproducible pattern of expansion, contraction, and memory formation. If the robustness of this pattern builds entirely on signals derived from other cell types or if activated T cells themselves contribute to the orchestration of these population dynamics-akin to bacterial quorum regulation-is unclear. Here, we examined this question using time-lapse microscopy, genetic perturbation, bioinformatic predictions, and mathematical modeling. We found that ICAM-1-mediated cell clustering enabled CD8+ T cells to collectively regulate the balance between proliferation and apoptosis. Mechanistically, T cell expressed CD80 and CD86 interacted with the receptors CD28 and CTLA-4 on neighboring T cells; these interactions fed two nested antagonistic feedback circuits that regulated interleukin 2 production in a manner dependent on T cell density as confirmed by in vivo modulation of this network. Thus, CD8+ T cell-population-intrinsic mechanisms regulate cellular behavior, thereby promoting robustness of population dynamics.


Assuntos
Antígenos CD28/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Animais , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular , Contagem de Células , Linhagem Celular , Sobrevivência Celular , Rastreamento de Células , Células Dendríticas/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Teóricos
5.
Nat Commun ; 11(1): 660, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005809

RESUMO

Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor ßγ (IL-2Rßγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rßγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.


Assuntos
Transferência Adotiva , Interleucina-2/análogos & derivados , Interleucina-2/agonistas , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Animais , Humanos , Interleucina-2/administração & dosagem , Interleucina-2/imunologia , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética
6.
Nat Commun ; 11(1): 661, 2020 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005826

RESUMO

High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rß). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Interleucina-2/análogos & derivados , Melanoma/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/administração & dosagem , Interleucina-2/agonistas , Interleucina-2/imunologia , Ipilimumab/administração & dosagem , Ativação Linfocitária/efeitos dos fármacos , Melanoma/genética , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Interleucina-2/genética , Receptores de Interleucina-2/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
PLoS One ; 15(1): e0227905, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978095

RESUMO

The pathogenesis of periodontitis (PD) involves several molecules of the immune system that interact in a network to eliminate the periodontopathogens, yet, they contribute to periodontal tissue destruction. The different mechanisms that lead to periodontal tissue damage are not clear. Despite this, immune response genes have been related to the development of PD previously, such as those involved in inflammasomes which are multiprotein complexes and cytokines including Interleukin-1. The aim of the study was to evaluate the polymorphisms in NLRP3 inflammasome, cytokine and receptor of cytokines genes in the development of periodontitis. This case-control study was conducted in 186 patients with PD (stage II and III and grade B) and 208 controls (localized gingivitis and periodontally healthy individuals). Genotyping was performed using PCR-RFLP for the SNP rs4612666 in NLRP3 and using PCR-SSP for IL1A, IL1B, IL1R, IL1RN, IL4RA, INFG, TGFB1, TNF, IL2, IL4, IL6, and IL10. Cytokine serum levels were measured using Luminex technology. SNPStats and OpenEpi software were used to perform statistical analysis. The higher frequencies of NLRP3 T/C and IL1B -511 T/T genotypes and IL2 (+166, -330) GT haplotype were observed in patients with PD compared to controls. The SNPs in NLRP3, IL1R +1970, IL6-174, TNF -308, IL2 +166 and -330, TGFB1 +869 and +915, IL4RA +1902, IL4-1098 and -590 were associated to PD in men. In conclusion, polymorphisms in NLRP3, IL1B and IL2 genes were associated to PD susceptibility. Men carrying the NLRP3, IL1R, IL6, TNF, IL2, TGFB1, IL4RA and IL4 polymorphisms had greater susceptibility than women for developing PD.


Assuntos
Interleucina-1beta/genética , Interleucina-2/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Periodontite/genética , Adulto , Citocinas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Inflamassomos/genética , Masculino , Pessoa de Meia-Idade , Periodontite/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Caracteres Sexuais , Fator de Crescimento Transformador beta1/genética
8.
PLoS One ; 15(1): e0227993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990927

RESUMO

OBJECTIVES: The regulatory mechanisms affecting the modulation of the immune system accompanying the progressive effort to exhaustion, particularly associated with T cells, are not fully understood. We analysed the impact of two progressive effort protocols on T helper (Th) cell distribution and selected cytokines. METHODS: Sixty-two male soccer players with a median age of 17 (16-29) years performed different protocols for progressive exercise until exhaustion: YO-YO (YYRL1) and Beep. Blood samples for all analyses were taken three times: at baseline, post-effort, and in recovery. RESULTS: The percentage of Th1 cells increased post-effort and in recovery. The post-effort percentage of Th1 cells was higher in the Beep group compared to the YYRL1 group. Significant post-effort increase in Th17 cells was observed in both groups. The post-effort percentage of regulatory T cells (Treg) increased in the Beep group. An increased post-effort concentration of IL-2, IL-6, IL-8 and IFN-γ in both groups was observed. Post-effort TNF-α and IL-10 levels were higher than baseline in the YYRL1 group, while the post-effort IL-17A concentration was lower than baseline only in the Beep group. The recovery IL-2, IL-4, TNF-α and IFN-γ levels were higher than baseline in the YYRL1 group. The recovery IL-4, IL-6, IL-8, TNF-α and IFN-γ values were higher than baseline in the Beep group. CONCLUSION: The molecular patterns related to cytokine secretion are not the same between different protocols for progressive effort. It seems that Treg cells are probably the key cells responsible for silencing the inflammation and enhancing anti-inflammatory pathways.


Assuntos
Esforço Físico/imunologia , Futebol/fisiologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adolescente , Adulto , Atletas , Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Esforço Físico/genética , Recuperação de Função Fisiológica/imunologia , Linfócitos T Reguladores/citologia , Células Th1/citologia , Células Th17/citologia , Células Th2/citologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Chem Pharm Bull (Tokyo) ; 68(1): 91-95, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902904

RESUMO

Magnolia Flower is a crude drug used for the treatment of headaches, toothaches, and nasal congestion. Here, we focused on Magnolia kobus, one of the botanical origins of Magnolia Flower, and collected the flower parts at different growth stages to compare chemical compositions and investigate potential inhibitory activities against interleukin-2 (IL-2) production in murine splenic T cells. After determining the structures, we examined the inhibitory effects of the constituents of the bud, the medicinal part of the crude drug, against IL-2 production. We first extracted the flower parts of M. kobus from the bud to fallen bloom stages and analysed the chemical compositions to identify the constituents characteristic to the buds. We found that the inhibitory activity of the buds against IL-2 production was more potent than that of the blooms. We isolated two known compounds, tiliroside (1) and syringin (2), characteristic to the buds from the methanol (MeOH) extract of Magnolia Flower. Moreover, we examined the inhibitory activities of both compounds against IL-2 production and found that tiliroside (1) but not syringin (2), showed strong inhibitory activity against IL-2 production and inhibited its mRNA expression. Thus, our strategy to examine the relationship between chemical compositions and biological activities during plant maturation could not only contribute to the scientific evaluation of medicinal parts of crude drugs but also assist in identifying biologically active constituents that have not yet been reported.


Assuntos
Interleucina-2/metabolismo , Magnolia/química , Extratos Vegetais/química , Animais , Linhagem Celular , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Flores/química , Flores/metabolismo , Glucosídeos/química , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Interleucina-2/genética , Magnolia/metabolismo , Camundongos , Fenilpropionatos/química , Fenilpropionatos/isolamento & purificação , Fenilpropionatos/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
10.
Immunity ; 52(1): 151-166.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924474

RESUMO

In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.


Assuntos
Granzimas/imunologia , Neoplasias/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Humanos , Interferon gama/imunologia , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/citologia , Microambiente Tumoral/imunologia
11.
Nat Commun ; 11(1): 113, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31913278

RESUMO

While antigen-primed T cells proliferate at speeds close to the physiologic maximum of mammalian cells, T cell memory is maintained in the absence of antigen by rare cell divisions. The transition between these distinct proliferative programs has been difficult to resolve via population-based analyses. Here, we computationally reconstruct the proliferative history of single CD8+ T cells upon vaccination and measure the division speed of emerging T cell subsets in vivo. We find that slower cycling central memory precursors, characterized by an elongated G1 phase, segregate early from the bulk of rapidly dividing effector subsets, and further slow-down their cell cycle upon premature removal of antigenic stimuli. In contrast, curtailed availability of inflammatory stimuli selectively restrains effector T cell proliferation due to reduced receptivity for interleukin-2. In line with these findings, persistence of antigenic but not inflammatory stimuli throughout clonal expansion critically determines the later size of the memory compartment.


Assuntos
Linfócitos T CD8-Positivos/citologia , Diferenciação Celular , Divisão Celular , Memória Imunológica , Subpopulações de Linfócitos T/citologia , Animais , Linfócitos T CD8-Positivos/imunologia , Ciclo Celular , Feminino , Interleucina-2/genética , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/imunologia
12.
PLoS One ; 15(1): e0226182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929537

RESUMO

People living with HIV (PLHIV) are at increased risk for cardiovascular disease (CVD), and immunity against cytomegalovirus (CMV) may be a contributing factor. We hypothesized that enhanced T-cell responses against CMV and CMV-IgG antibody-levels are associated with higher arterial blood pressure in PLHIV. We assessed serum CMV-IgG, systolic- (SBP) and diastolic- (DBP) blood pressure, pulse pressure (PP), traditional risk factors, activated CD8+ T-cells (CD38+HLA-DR+), senescent CD8+ T-cells (CD28-CD57+) and interleukin-6 (IL-6) in 60 PLHIV and 31 HIV-uninfected controls matched on age, gender, education and comorbidity. In PLHIV, expression of interleukin-2, tumor necrosis factor-α and interferon-γ was measured by intracellular-cytokine-staining after stimulation of T-cells with CMV-pp65 and CMV-gB. Associations between CMV-specific immune responses and hypertension, SBP, DBP or PP were assessed by multivariate logistic and linear regression models adjusted for appropriate confounders. The median age of PLHIV was 47 years and 90% were male. Prevalence of hypertension in PLHIV was 37% compared to 55% of HIV-uninfected controls. CMV-specific CD8+ T-cell responses were independently associated with higher PP (CMV-pp65; ß = 2.29, p = 0.001, CMV-gB; ß = 2.42, p = 0.001) in PLHIV. No significant differences were found with regard to individual measures of SBP and DBP. A possible weak association was found between CMV-IgG and hypertension (ß = 1.33, p = 0.049) after adjustment for age, smoking and LDL-cholesterol. HIV-related factors, IL-6, CD8+ T-cell activation or CD8+ T-cell senescence did not mediate the associations, and no associations were found between CMV-specific CD4+ T-cell responses and blood pressure in PLHIV. In conclusion, increased arterial blood pressure in PLHIV may be affected by heightened CMV-specific CD8+ T-cell responses.


Assuntos
Pressão Sanguínea , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/imunologia , Infecções por HIV/patologia , Adulto , Anticorpos Antivirais/sangue , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Senescência Celular , Citomegalovirus/metabolismo , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/patologia , Feminino , Infecções por HIV/complicações , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Hipertensão/patologia , Interleucina-2/análise , Interleucina-6/sangue , Modelos Logísticos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Proteínas da Matriz Viral/imunologia
14.
Proc Natl Acad Sci U S A ; 117(1): 285-291, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871161

RESUMO

The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αß TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.


Assuntos
Ativação Linfocitária/efeitos dos fármacos , Nanopartículas/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/efeitos dos fármacos , Complexo Receptor-CD3 de Antígeno de Linfócitos T/metabolismo , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Antígenos CD28/metabolismo , Complexo CD3/química , Complexo CD3/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Fosforilação , Complexo Receptor-CD3 de Antígeno de Linfócitos T/química , Complexo Receptor-CD3 de Antígeno de Linfócitos T/genética , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
15.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(10): 1107-1112, 2019 Oct 28.
Artigo em Chinês | MEDLINE | ID: mdl-31857503

RESUMO

OBJECTIVE: To analyze the components of tumor infiltrating T lymphocyte (TIL) cells in malignant pleural effusion of lung adenocarcinoma, and evaluate their killing activities to autologous tumor cells. 
 Methods: Malignant pleural effusions were collected from 17 patients with lung adenocarcinoma. Mononuclear cells were isolated by Ficoll density gradient centrifugation and flow cytometer was used to analyze TIL cell components. TIL and tumor cells were separated through adherent culture. The tumor cells were identified via intramuscular injection of adherent cells into nude mice and the killing effect of cultured lymphocytes on autologous tumor cells was studied.
 Results: Of the TIL in malignant pleural effusions, T cells accounted for 60.6%-79.3%, while T helper cells were significantly higher than T killer cells (36.63%±1.90% vs 24.64%±2.32%, P<0.001). There were also natural killer (NK) cells and NK T cells in the effusions. Tumor cells were successfully isolated and cultured. The killing activity of cultured TIL to autologous tumor cells was 39.14%±12.04%, and the killing activity of TIL with high proliferation rate to autologous tumor cells was higher than that of low proliferation group (50.51%±3.80% vs 29.04%±5.77%, P<0.001).
 Conclusion: T lymphocytes are the major components of TIL in malignant pleural effusions derived from lung adenocarcinoma, and T helper cells are more than T killer cells. The killing activity of TIL with strong proliferation ability to autologous tumor cells is higher than that of TIL with weak proliferation ability. Therefore, cells from malignant pleural effusions could be used for cellular immunotherapy against tumor.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Derrame Pleural Maligno , Animais , Citotoxicidade Imunológica , Humanos , Interleucina-2 , Camundongos , Camundongos Nus , Linfócitos T
16.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(6): 821-826, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31880112

RESUMO

OBJECTIVE: To study the impact of atypical protein kinase Cι (PKCι) isoform PKC on the pancreatic cancer cells towards the tumoricidal effect of cytokine-induced killer (CIK) cells and explore its mechanisms. METHODS: CIK cells were prepared by inducing mononuclear cells isolated from the peripheral blood of healthy people with interleukin-2 (IL-2), interferon (IFN) and CD3 mAb and subsequently co-cultured with pancreatic epithelial cell HPDE6-C7, pancreatic cancer cells MiaPaCa and PANC-1 with or without PKC inhibitor named sodium thiomalate (ATM). All cells were divided into control group, ATM group, co-culture group with CIK and co-culture group with CIK+ATM. Cell count was used to detect the growth of each group from 1 to 8 d. Flow cytometry was used to detect the death rate of the cell lines after 48 h cell culture in each group. The small hairpin RNA (shRNA) was used for PKCι knockdown and the recombinant plasmid transfection was for PKCι overexpression in pancreatic cancer cells. Western blot and real-time fluorescent quantitative PCR (qRT-PCR) were utilized to determine the expression of PKCι protein and the impact on gene expression of transforming growth factor-ß (TGF-ß), a downstream effector modulated by PKC. Different mass concentrations of TGF-ß (1, 10, 20 ng/mL) were added into the co-culture of MiaPaCa and PANC-1 with CIK. The cell death rate was detected by flow cytometry 48 h later, so as to explore the possible mechanisms of the impact of PKCι on the tumoricidal effects of CIK cells. RESULTS: ATM and CIK were shown to suppress the growth and induce apoptosis or death of pancreatic cancer cells, meanwhile, ATM can enhance the tumoricidal effect of CIK on pancreatic cancer cells. Moreover, we found that PKCι knockdown in pancreatic cancer cells can down-regulate the gene expression of TGF-ß. In return, PKCι overexpression in pancreatic cancer cells can increase the gene expression of TGF-ß. The death rate of cancer cells with 10, 20 ng/mL TGF-ß was lower compared with the control group (P < 0.05). CONCLUSIONS: PKCι knockdown in pancreatic cancer cells can not only inhibit the growth of pancreatic cancer cells, but also enhance the tumoricidal effects of CIK on cancer cells. The possible mechanism of PKCι is to affect the immune escape of tumor cells by regulating the expression of TGF-ß.


Assuntos
Células Matadoras Induzidas por Citocinas , Neoplasias Pancreáticas , Apoptose , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Interleucina-2
17.
Biomed Res Int ; 2019: 1703842, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871930

RESUMO

Systemic lupus erythematosus (SLE) is characterized by systemic end-organ damage. We investigated the involvement of IRF5, TLR-7, MECP2, STAT4, and TNFSF4 genes and TNF-α, IFN-γ, IL-2, IL-12, IL-6, and IL-10 cytokines in SLE pathogenesis and in organ damage in Jordanian patients. Blood was collected from 51 patients and 50 controls. Expression levels of SLE genes in PBMCs and cytokine levels were determined using RT-PCR and ELISA, respectively. Expression levels of all genes and levels of TNF-α, IL-12, IL-6, and IL-10 were higher in SLE patients than those in controls (p < 0.05), whereas IL-2 level was lower. High STAT4 (α), TNFSF4, and IL-10 levels correlated with cardiovascular damage, and high MECP2 (α) and TNF-α correlated with renal damage. Pulmonary and musculoskeletal damages correlated with high levels of TNFSF4. We concluded that STAT4 and TNFSF4 genes with TNF-α and IL-10 cytokines could be used as biomarkers to assess SLE activity and manage treatment.


Assuntos
Citocinas/metabolismo , Fatores Reguladores de Interferon/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Ligante OX40/metabolismo , Fator de Transcrição STAT4/metabolismo , Receptor 7 Toll-Like/metabolismo , Adulto , Biomarcadores/sangue , Citocinas/sangue , Feminino , Regulação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/genética , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Jordânia , Lúpus Eritematoso Sistêmico/genética , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Ligante OX40/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT4/genética , Receptor 7 Toll-Like/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
Immunity ; 51(6): 1102-1118.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31757673

RESUMO

Young children are more susceptible to developing allergic asthma than adults. As neural innervation of the peripheral tissue continues to develop after birth, neurons may modulate tissue inflammation in an age-related manner. Here we showed that sympathetic nerves underwent a dopaminergic-to-adrenergic transition during post-natal development of the lung in mice and humans. Dopamine signaled through a specific dopamine receptor (DRD4) to promote T helper 2 (Th2) cell differentiation. The dopamine-DRD4 pathway acted synergistically with the cytokine IL-4 by upregulating IL-2-STAT5 signaling and reducing inhibitory histone trimethylation at Th2 gene loci. In murine models of allergen exposure, the dopamine-DRD4 pathway augmented Th2 inflammation in the lungs of young mice. However, this pathway operated marginally after sympathetic nerves became adrenergic in the adult lung. Taken together, the communication between dopaminergic nerves and CD4+ T cells provides an age-related mechanism underlying the susceptibility to allergic inflammation in the early lung.


Assuntos
Neurônios Adrenérgicos/citologia , Asma/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Pulmão/patologia , Células Th2/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Asma/imunologia , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Interleucina-2/metabolismo , Interleucina-4/imunologia , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores de Dopamina D4/metabolismo , Fator de Transcrição STAT5/metabolismo , Sistema Nervoso Simpático/citologia
19.
Cell Biochem Funct ; 37(8): 618-624, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31710117

RESUMO

The aim of this study was to investigate the effect of vaccinia virus expressing IL-37 (VV-IL-37) on cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) and its possible underlying molecular mechanisms. In this study, we constructed a cancer-targeted vaccinia virus carrying the IL-37 gene knocked in the region of the viral thymidine kinase (TK) gene. Human HCC cell lines were assayed in vitro for cell proliferation, migration and invasion. Serum level, relative mRNA level and protein level of IL-37 in HCC cell lines SMMC7721 and Bel7402 were tested by ELISA assay, qRT-PCR and western blot, respectively. The levels of IL-2, IFN-γ and TNF-α in HCC tumor tissues were also analyzed by ELISA. STAT3 and p-STAT3 expression in tumor tissues were determined by western blot. Our results showed that VV-IL-37 efficiently infected and inhibited HCC cells proliferation, migration and invasion via decreasing STAT3 phosphorylation. In vivo, VV-IL-37 expressed IL-37 at a high level in the transplanted tumor, reduced STAT3 activity, and eventually inhibited tumor growth. In conclusion, we demonstrate that VV-IL-37 promotes antitumor immune responses in HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Interleucina-1/metabolismo , Neoplasias Hepáticas/patologia , Vírus Vaccinia/fisiologia , Animais , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Interferon gama/metabolismo , Interleucina-1/genética , Interleucina-2/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fator de Transcrição STAT3/metabolismo , Transplante Heterólogo , Vírus Vaccinia/genética
20.
Medicine (Baltimore) ; 98(42): e17506, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626107

RESUMO

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has produced promising response rates in patients with B cell malignancies. However, previous meta-analyses have demonstrated that CAR T-cell efficacy is unsatisfactory in patients with lymphoma unlike in patient with other hematological malignancies, but these studies included insufficient numbers of studies and patients with lymphoma. Furthermore, clinicians are interested in the effects of infusion dose, CAR structure, interleukin-2 (IL-2), and conditioning therapy regimen. METHODS: All clinical trials administering autologous CAR T-cell therapy in lymphoma patients were searched in medical databases. A traditional meta-analysis was performed to assess the safety and efficacy of CAR T-cells in lymphoma treatment. Subgroup analysis was performed to determine the relationships between potential factors and efficacy. The best overall response rate (ORR), 6 month ORR (6m ORR), and severe cytokine release syndrome (sCRS) rate were calculated by Stata 14.0. RESULTS: A total of 411 patients across all the studies were included. Our analysis showed a best ORR of 0.71, a 6m ORR of 0.63, and an overall CRS (grade ≥ 3) rate of 0.18. The subgroup analysis showed that increased response rates and reduced CRS (grade ≥ 3) rates were associated with a low dose of CAR T-cells. No IL-2 administration and the use of a fludarabine-containing lymphodepletion regimen led to improved efficacy, while anti-CD19 CAR T cells led to a more successful outcome than anti-CD20 CAR T cells. In addition, 2nd- and 3rd-generation CAR T cells exhibited increased effectiveness in clinical studies, and no significant effect diversity was found between the 2nd- and 3rd-generation CAR T cells. sCRS was associated with a high dose of infused CAR T cells when IL-2 and fludarabine were excluded from the positive factors for sCRS. CONCLUSION: CAR T cells are promising in the treatment of relapsed or refractory lymphoma. Doses lower than 10/m, no IL-2 administration, fludarabine administration, and anti-CD19 CAR T cells were related to improved efficacy and safety.


Assuntos
Imunoterapia Adotiva/métodos , Linfoma/terapia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos Quiméricos/administração & dosagem , Humanos , Interleucina-2/imunologia , Linfoma/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Resultado do Tratamento
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