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1.
Oxid Med Cell Longev ; 2022: 3185320, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35726331

RESUMO

Objective: To compare the merits and demerits of PEG-IFNα-2a and PEG-IFNα-2b for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). Methods: Clinical files from eighty-four CHB patients admitted to the Second Hospital of Shanxi Medical University between January 2018 and January 2019 were retrospectively analyzed and assigned to two groups: group 2a treated with PEG-IFNα-2a and group 2b treated with PEG-IFNα-2b. The clinical efficacy was compared between the above two arms, and the liver function (ALT, AST, HA, LN, and IV-C), HBV-DNA, HBsAg, HBeAg, and inflammatory factors (IFs, IL-1ß, IL-6, IL-8, and TNF-α) were tested at 12 weeks (T1), 24 weeks (T2), and 48 weeks (T3). The alterations of hemodynamics (SBP, DBP, MAP, and CVP), cardiac function (LVEF and BNP), and the incidence of adverse reactions (ARs) during treatment were recorded. Finally, the patients were followed up for 2 years to investigate the quality of life (QOL) as well as the positive seroconversion rate of HBsAg and HBeAg. Results: The overall response rate was similar in the two arms (P > 0.05). After treatment, the liver function, HBV-DNA, HBsAg, HBeAg, IFs, hemodynamics, and cardiac function were enormously improved (P < 0.05), with faster improvement in group 2b compared with group 2a (P < 0.05). The investigation of ARs identified notably lower incidence rates of alopecia, thrombocytopenia, and granulocytopenia in group 2a as compared to group 2b (P < 0.05). The prognostic follow-up results revealed no distinct difference in the QOL score and the positive seroconversion rate of HBsAg and HBeAg (P > 0.05); however, the quantitative results of HBV-DNA, HBsAg, and HBeAg in group 2b were lower than those in group 2a (P < 0.05). Conclusions: Both PEG-IFNα-2a and PEG-IFNα-2b have excellent and stable therapeutic effects on HBeAg-positive CHB, among which PEG-IFNα-2b renders a faster treatment process but higher side effects, which can provide valuable references when choosing a treatment plan for CHB.


Assuntos
Antivirais , Hepatite B Crônica , Interferon alfa-2 , Antivirais/uso terapêutico , DNA Viral , Hemodinâmica , Antígenos de Superfície da Hepatite B , Antígenos E da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa , Polietilenoglicóis , Qualidade de Vida , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
2.
Biomolecules ; 12(6)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35740960

RESUMO

Pathogenesis-related (PR) proteins produced in plants play a crucial role in self-defense against microbial attacks. Previously, we have identified a novel PR-1-like protein (OPRP) from Oenanthe javanica and examined its pharmacologic relevance and cell signaling in mammalian cells. Purified full-length OPRP protein significantly increased toll-like receptor 4 (TLR4)-dependent expression levels of genes such as inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and CD80. We also found that small peptides (OPRP2 and OPRP3) designed from OPRP remarkably upregulated myxovirus resistance (Mx1), 2'-5' oligoadenylate sythetase (OAS), and interferon (IFN) α/ß genes in mouse splenocytes as well as human epithelial cells. Notably, OPRP protein distinctively activated STAT1 phosphorylation and ISGF-3γ. Interestingly, OPRP2 and OPRP3 were internalized to the cytoplasm and triggered dimerization of STAT1/STAT2, followed by upregulation of type I IFN-dependent antiviral cytokines. Moreover, OPRP1 successfully inhibited viral (Pseudo SARS-CoV-2) entry into host cells. Taken together, we conclude that OPRP and its small peptides (OPRP1 to 3) present a new therapeutic intervention for modulating innate immune activity through type I IFN-dependent antiviral signaling and a new therapeutic approach that drives an antiviral state in non-immune cells by producing antiviral cytokines.


Assuntos
COVID-19 , Oenanthe , Animais , Antivirais/farmacologia , Citocinas/metabolismo , Imunidade Inata , Interferon-alfa/farmacologia , Interferon beta/farmacologia , Mamíferos/metabolismo , Camundongos , Oenanthe/metabolismo , SARS-CoV-2 , Transdução de Sinais
3.
J Transl Med ; 20(1): 253, 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35659704

RESUMO

BACKGROUND: We hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME). PATIENTS AND METHODS: This gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male). RESULTS: The subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1ß (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244). CONCLUSION: Female gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www. CLINICALTRIALS: gov/ct2/show/NCT01274338.


Assuntos
Melanoma , Neoplasias Cutâneas , Adjuvantes Imunológicos/uso terapêutico , Antígeno CTLA-4/genética , Feminino , Humanos , Interferon-alfa , Ipilimumab/uso terapêutico , Leucócitos Mononucleares/patologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Microambiente Tumoral
4.
Front Immunol ; 13: 891424, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663955

RESUMO

Objective: The ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy. Methods: A single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy. Results: Of 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment. Conclusion: The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Antivirais/uso terapêutico , DNA Viral , Células Dendríticas/metabolismo , Antígenos E da Hepatite B , Humanos , Interferon-alfa , Polietilenoglicóis , Estudos Prospectivos , Proteínas Recombinantes
5.
J Virol ; 96(12): e0052822, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35604219

RESUMO

Foot-and-mouth disease (FMD) is an acute contagious disease that affects cloven-hoofed animals and has severe global economic consequences. FMD is most commonly controlled by vaccination. Currently available commercial FMD vaccines contain chemically inactivated whole viruses, which are thought to be slow acting as they are effective only 4 to 7 days following vaccination. Hence, the development of a novel rapid vaccine or alternative measures, such as antiviral agents or the combination of vaccines and antiviral agents for prompt FMD virus (FMDV) outbreak containment, is desirable. Here, we constructed a recombinant baculovirus (BacMam) expressing consensus porcine interferon alpha (IFN-α) that has three additional N-glycosylation sites driven by a cytomegalovirus immediate early (CMV-IE) promoter (Bac-Con3N IFN-α) for protein expression in mammalian cells. Bac-Con3N IFN-α expressing highly glycosylated porcine IFN-α protein increased the duration of antiviral effects. We evaluated the antiviral effects of Bac-Con3N IFN-α in swine cells and mice and observed sustained antiviral effects in pig serum; additionally, Bac-Con3N IFN-α exhibited sustained antiviral effects in vivo as well as adjuvant effects in combination with an inactivated FMD vaccine. Pigs injected with a combination of Bac-Con3N IFN-α and the inactivated FMD vaccine were protected against FMDV at 1, 3, and 7 days postvaccination. Furthermore, we observed that in combination with the inactivated FMD vaccine, Bac-Con3N IFN-α increased neutralizing antibody levels in mice and pigs. Therefore, we suggest that Bac-Con3N IFN-α is a strong potential antiviral and adjuvant candidate for use in combination with inactivated FMD vaccines to protect pigs against FMDV. IMPORTANCE Early inhibition of foot-and-mouth disease (FMD) virus (FMDV) replication in pigs is highly desirable as FMDV transmission and shedding rates are higher in pigs than in cattle. However, commercial FMD vaccines require at least 4 to 7 days postvaccination (dpv) for protection, and animals are vulnerable to heterologous viruses before acquiring high antibody levels after the second vaccination. Therefore, the development of antiviral agents for use in combination with FMD vaccines is essential. We developed a novel antiviral and immunostimulant, Bac-Con3N IFN-α, which is a modified porcine IFN-α-expressing recombinant baculovirus, to improve IFN stability and allow its direct delivery to animals. We present a promising candidate for use in combination with inactivated FMD vaccines as pigs applied to the strategy had early protection against FMDV at 1 to 7 dpv, and their neutralizing antibody levels were higher than those in pigs administered the vaccine only.


Assuntos
Vírus da Febre Aftosa , Febre Aftosa , Interferon-alfa , Vacinas Virais , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Antivirais/farmacologia , Baculoviridae , Febre Aftosa/imunologia , Febre Aftosa/prevenção & controle , Interferon-alfa/farmacologia , Camundongos , Suínos , Vacinas de Produtos Inativados
6.
Korean J Gastroenterol ; 79(5): 222-227, 2022 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-35610553

RESUMO

Primary esophageal melanoma is a rare disease with a poor prognosis. To date, 18 cases have been reported in Korea. Four patients visited the Chonnam National University Hwasun Hospital with dysphagia, followed by epigastric pain and discomfort, odynophagia, and weight loss. Esophagogastroduodenoscopy revealed a black pigmented polypoid mass, protruding mass, or black-pigmented flat lesions. Two patients had distant metastases and lymphadenopathies in imaging studies. Two patients underwent esophagectomy and intrathoracic esophagogastrostomy. One patient was treated with chemotherapy and interferon-alpha. The other patient declined further treatment. The routine histology using H&E revealed brown-colored atypical melanocytes. Immunohistochemical staining exhibited strong reactivity for Melan-A, S-100, and HMB-45 proteins. The biopsy specimens were interpreted to be malignant melanoma. One patient had multiple distant metastases 13 months after surgery. The other patient had no recurrence for 33 months after surgery. The patient treated with chemotherapy and interferon-alpha showed disease progression in the follow-up examination. Primary esophageal melanoma in Korea is a rare disease characterized by aggressive behavior, early metastasis, and poor prognosis.


Assuntos
Transtornos de Deglutição , Neoplasias Esofágicas , Melanoma , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Humanos , Interferon-alfa/uso terapêutico , Melanoma/diagnóstico , Melanoma/patologia , Melanoma/terapia , Prognóstico , Doenças Raras , República da Coreia
7.
Aliment Pharmacol Ther ; 56(1): 144-154, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35514008

RESUMO

BACKGROUND AND AIM: Bulevirtide (BLV) blocks the uptake of the hepatitis D virus (HDV) into hepatocytes via the sodium/bile acid cotransporter NTCP. BLV was conditionally approved by the EMA but real-life data on BLV efficacy are limited. METHODS: Patients were treated with BLV monotherapy. Patients who did not achieve further decreases in HDV-RNA after 24 weeks were offered PEG-IFN as an add-on therapy in a response-guided manner. RESULTS: Twenty-three patients (m: 10, f: 13; mean age: 47.9 years, cirrhosis: 16; median ALT: 71 IU/ml; median HDV-RNA: 2.1 × 105 copies/ml) started BLV monotherapy (2 mg/day: 22; 10 mg/day: 1). Twenty-two completed ≥24 weeks of treatment (24-137 weeks): Ten (45%) were classified as BLV responders at week 24. BLV was stopped in two patients with >6 months HDV-RNA undetectability, but both became HDV-RNA positive again. One patient was transplanted at week 25. One patient terminated treatment because of side effects at week 60. Ten patients are still on BLV monotherapy. Adding PEG-IFN in eight patients induced an HDV-RNA decrease in all (1.29 ± 0.19 [SD] log within 12 weeks). HDV-RNA decreased by >2log or became undetectable in 45%(10/22), 55%(11/20), 65% (13/20) and 69% (9/13); and ALT levels normalised in 64% (14/22), 85% (17/20), 90% (18/20) and in 92% (12/13) patients at weeks 24, 36, 48 and 60, respectively. Portal pressure decreased in 40% (2/5) of patients undergoing repeated measurement under BLV therapy. CONCLUSION: Long-term BLV monotherapy is safe and effectively decreases HDV-RNA and ALT-even in patients with cirrhosis. The optimal duration of BLV treatment alone or in combination with PEG-IFN remains to be established. An algorithm for a response-guided BLV treatment approach is proposed.


Assuntos
Hepatite D Crônica , Antivirais , Hepatite D Crônica/tratamento farmacológico , Vírus Delta da Hepatite/genética , Humanos , Interferon-alfa/uso terapêutico , Lipopeptídeos , Cirrose Hepática/tratamento farmacológico , Pessoa de Meia-Idade , RNA Viral/genética , Resultado do Tratamento
8.
EBioMedicine ; 80: 104047, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35561451

RESUMO

BACKGROUND: Type I interferon (IFN-I) production by plasmacytoid dendritic cells (pDCs) occurs during viral infection, in response to Toll-like receptor 7 (TLR7) stimulation and is more vigorous in females than in males. Whether this sex bias persists in ageing people is currently unknown. In this study, we investigated the effect of sex and aging on IFN-α production induced by PRR agonist ligands. METHODS: In a large cohort of individuals from 19 to 97 years old, we measured the production of IFN-α and inflammatory cytokines in whole-blood upon stimulation with either R-848, ODN M362 CpG-C, or cGAMP, which activate the TLR7/8, TLR9 or STING pathways, respectively. We further characterized the cellular sources of IFN-α. FINDINGS: We observed a female predominance in IFN-α production by pDCs in response to TLR7 or TLR9 ligands. The higher TLR7-driven IFN-α production in females was robustly maintained across ages, including the elderly. The sex-bias in TLR9-driven interferon production was lost after age 60, which correlated with the decline in circulating pDCs. By contrast, STING-driven IFN-α production was similar in both sexes, preserved with aging, and correlated with circulating monocyte numbers. Indeed, monocytes were the primary cellular source of IFN-α in response to cGAMP. INTERPRETATION: We show that the sex bias in the TLR7-induced IFN-I production is strongly maintained through ages, and identify monocytes as the main source of IFN-I production via STING pathway. FUNDING: This work was supported by grants from Région Occitanie/Pyrénées-Méditerranée (#12052910, Inspire Program #1901175), University Paul Sabatier, and the European Regional Development Fund (MP0022856).


Assuntos
Interferon-alfa , Monócitos , Receptor 7 Toll-Like , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Interferon-alfa/biossíntese , Interferon-alfa/sangue , Interferon-alfa/imunologia , Ligantes , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Receptor Toll-Like 9/metabolismo , Adulto Jovem
9.
PLoS Negl Trop Dis ; 16(5): e0010426, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35536870

RESUMO

During 2015-2016, outbreaks of Zika virus (ZIKV) occurred in Southeast Asia and the Americas. Most ZIKV infections in humans are asymptomatic, while clinical manifestation is usually a self-limiting febrile disease with maculopapular rash. However, ZIKV is capable of inducing a range of severe neurological complications collectively described as congenital Zika syndrome (CZS). Notably, the scale and magnitude of outbreaks in Southeast Asia were significantly smaller compared to those in the Americas. Sequence comparison between epidemic-associated ZIKV strains from Southeast Asia with those from the Americas revealed a methionine to valine substitution at residue position 114 of the NS5 protein (NS5-M114V) in all the American isolates. Using an American isolate of ZIKV (Natal), we investigated the impact of NS5-M114V mutation on virus replication in cells, virulence in interferon (IFN) α/ß receptor knockout (Ifnar-/-) mice, as well as replication and transmission potential in Aedes aegypti mosquitoes. We demonstrated that NS5-M114V mutation had insignificant effect on ZIKV replication efficiency in cells, its ability to degrade STAT2, and virulence in vivo, albeit viremia was slightly prolonged in mice. Furthermore, NS5-M114V mutation decreased mosquito infection and dissemination rates but had no effect on virus secretion into the saliva. Taken together, our findings support the notion that NS5-M114V mutation is unlikely to be a major determinant for virus replication and transmission potential.


Assuntos
Aedes , Infecção por Zika virus , Zika virus , Animais , Interferon-alfa , Interferon beta/genética , Camundongos , Mosquitos Vetores , Mutação , Estados Unidos , Replicação Viral
10.
Proc Natl Acad Sci U S A ; 119(20): e2011665119, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35549556

RESUMO

APOBEC3A (A3A) is a cytidine deaminase that inactivates a variety of viruses through introduction of lethal mutations to the viral genome. Additionally, A3A can suppress HIV-1 transcription in a deaminase-independent manner by binding to the long terminal repeat of proviral HIV-1. However, it is unknown whether A3A targets additional host genomic loci for repression. In this study, we found that A3A suppresses gene expression by binding TTTC doublets that are in close proximity to each other. However, one TTTC motif is sufficient for A3A binding. Because TTTC doublets are present in interferon (IFN)-stimulated response elements (ISRE), we hypothesized that A3A may impact IFN-stimulated gene (ISG) expression. After scanning the human genome for TTTC doublet occurrences, we discovered that these motifs are enriched in the proximal promoters of genes associated with antiviral responses and type I IFN (IFN-I) signaling. As a proof of principle, we examined whether A3A can impact ISG15 expression. We found that A3A binding to the ISRE inhibits phosphorylated STAT-1 binding and suppresses ISG15 induction in response to IFN-I treatment. Consistent with these data, our RNA-sequencing analyses indicate that A3A loss results in increased IFN-I­dependent induction of several ISGs. This study revealed that A3A plays an unexpected role in ISG regulation and suggests that A3A contributes to a negative feedback loop during IFN signaling.


Assuntos
Citidina Desaminase , Citocinas , Regulação da Expressão Gênica , Interferon-alfa , Ubiquitinas , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Citocinas/genética , Humanos , Interferon-alfa/metabolismo , Interferon-alfa/farmacologia , Elementos de Resposta , Ubiquitinas/genética
11.
Viruses ; 14(5)2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35632770

RESUMO

Viruses have evolved diverse strategies to evade the antiviral response of interferons (IFNs). Exogenous IFNs were applied to eliminate the counteracting effect and possess antiviral properties. Caprine parainfluenza virus 3 (CPIV3) and bovine parainfluenza virus type 3 (BPIV3) are important pathogens associated with respiratory diseases in goat and cattle, respectively. To explore the feasibility of type I IFNs for control of CPIV3 and BPIV3 infection, the activated effects of IFN-stimulated genes (ISGs) and the immunomodulation responses of goat IFN-α were detected by transcriptomic analysis. Then, the antiviral efficacy of goat IFN-α and IFN-τ against CPIV3 and BPIV3 infection in MDBK cells was evaluated using different treatment routes at different infection times. The results showed that CPIV3 infection inhibited the production of type I IFNs, whereas exogenous goat IFN-α induced various ISGs, the IFN-τ encoding gene, and a negligible inflammatory response. Consequently, goat IFN-α prophylaxis but not treatment was found to effectively modulate CPIV3 and BPIV3 infection; the protective effect lasted for 1 week, and the antiviral activity was maintained at a concentration of 0.1 µg/mL. Furthermore, the antiviral activity of goat IFN-τ in response to CPIV3 and BPIV3 infection is comparable to that of goat IFN-α. These results corroborate that goat IFN-α and IFN-τ exhibit prophylactic activities in response to ruminant respiratory viral infection in vitro, and should be further investigated for a potential use in vivo.


Assuntos
Interferon Tipo I , Infecções por Paramyxoviridae , Animais , Antivirais/farmacologia , Bovinos , Cabras , Interferon Tipo I/genética , Interferon-alfa/farmacologia , Vírus da Parainfluenza 3 Humana/fisiologia
12.
J Immunol Res ; 2022: 3647817, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600045

RESUMO

Objective: To analyze the role of PD-1/PD-L1 signaling pathway in regulating T cell activation and secretion of proinflammatory factors in atrial fibrillation. Methods: Forty-five patients with atrial fibrillation admitted to the cardiology department of our hospital from July 2019 to March 2021 were selected to be included in the atrial fibrillation group, and another 45 healthy volunteers were selected as the control group to compare the changes of T cell CD69 and human leukocyte antigen-DR (HLA-DR) expression in the peripheral blood of the two study groups; compare the changes of programmed death factor-1 on CD4+ and CD8+ lymphocytes in the peripheral blood of the two groups (PD-1) expression changes and PD-L1 and PD-L2 expression changes on peripheral blood myeloid dendritic cells (mDCs) cells; compare the changes of interleukin-2, interleukin-6, interleukin-10, and interleukin-17A (IL-2, IL-6, IL-10, and IL-17), tumor necrosis factor (TNF), and interferon gamma (IFN-γ) concentrations on peripheral blood inflammatory factors in the two groups; and isolate the two groups of peripheral blood mDCs cells; α interferon upregulated PD-L1 expression in the cells and analyzed the effect of PD-L1 expression on the ability of mDCs to stimulate T cells to secrete cytokines. Results: The positive expression rates of CD69 and HLA-DR on peripheral blood CD3+ T lymphocytes were significantly higher in patients in the atrial fibrillation group than in the control group, and the differences were statistically significant (P < 0.01). The positive expression rate of PD-1 on CD4+ lymphocytes was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01). There was no statistically significant difference between the two groups in terms of PD-1 positive expression rate on CD8+ lymphocytes (P > 0.05). The positive expression rate of PD-L1 on mDCs cells was significantly lower in patients in the atrial fibrillation group than in the control group (P < 0.01), and there was no statistically significant difference between the two groups in the positive expression rate of PD-L2 on mDCs cells, PD-L1, and PD-L2 on CD4+ and CD8+ T cells (P > 0.05). The concentrations of IL-2, IL-6, IL-10, and IFN-γ in peripheral blood were significantly higher in patients in the atrial fibrillation group than in the control group (P < 0.05), and there was no statistically significant difference in the comparison of IL-17A and TNF concentrations in peripheral blood between the two groups (P > 0.05). In the atrial fibrillation group, the ability of mDCs to stimulate T cells to secrete IL-2 and IFN-γ was significantly higher, and the ability to secrete IL-10 was significantly lower compared with the control group (P < 0.05). After α interferon upregulated PD-L1 expression in cells, the ability of mDCs to stimulate T cells to secrete IL-2, IL-10, and IFN-γ cytokines was reversed in patients in the atrial fibrillation group, and the differences compared with the control group were not statistically significant (P > 0.05). Conclusion: PD-1/PD-L1 signaling pathway may play an immunomodulatory role in the pathogenesis of atrial fibrillation by promoting increased secretion of inflammatory factors through regulating T cell activation.


Assuntos
Fibrilação Atrial , Antígeno B7-H1 , Fibrilação Atrial/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Humanos , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Ativação Linfocitária , Receptor de Morte Celular Programada 1/metabolismo
13.
Front Immunol ; 13: 892031, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603222

RESUMO

Objective: To explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods: It was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment. Results: Among 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001). Conclusion: Dynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.


Assuntos
Antígenos de Superfície da Hepatite B , Hepatite B Crônica , Biomarcadores , Citocinas , DNA Viral , Anticorpos Anti-Hepatite B , Antígenos E da Hepatite B , Humanos , Interferon-alfa , Interleucina-10 , Polietilenoglicóis , Estudos Prospectivos , Proteínas Recombinantes
14.
Biomed Res Int ; 2022: 6054677, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35572735

RESUMO

Introduction: Direct-acting antivirals (DAAs) have significantly improved the efficacy and tolerability of the treatment of hepatitis C virus (HCV). However, studies conducted on actual patients with the aim of predicting the risk associated with treatment failure are lacking. Methods: Our study enrolled 334 new HCV patients and assessed the effectiveness of treatment and predicted the risk of failure to achieve sustained virological response (SVR) by developing a multiple logistic model. Our study compared the variables between the two groups, those who did (group 0, n = 239) and did not achieve SVR (group 1, n = 95). Results: The cure rate of HCV at 12th week in our study was 71.56%. We found that advanced cirrhosis, HCV genotype, HBV coinfection, rapid virological response (RVR), fibrosis index (FIB-4) score, serum levels of AST, ALP, hemoglobin, and viral load before treatment were prognostic factors associated with rate of failure to achieve SVR at week 12 of DAA therapy. In the multiple logistic model, eight significant predictors including advanced cirrhosis status, HCV genotype, RVR, AST/ALP levels, FIB-4 score, and viral load before treatment predicted the risk of failure with excellent model performance (area under the receiver operating characteristic curve (AUCROC) [95% CI] =0.986 (0.971-0.999)). RVR and advanced cirrhosis were the two strongest predictors with odd ratios (95% CI) =9.72 (2.8, 39.28) and 51.54 (6.39, 139.82), respectively. Conclusion: The multiple logistic regression model included significant factors to estimate the probability of failure to achieve SVR, which could improve HCV treatment strategy.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Interferon-alfa/genética , Cirrose Hepática/complicações , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Ribavirina/uso terapêutico , Fatores de Risco , Resultado do Tratamento
15.
J Hepatol ; 76(6): 1249-1262, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35589248

RESUMO

Functional cure of hepatitis B is defined as sustained undetectable circulating HBsAg and HBV DNA after a finite course of treatment. Barriers to HBV cure include the reservoirs for HBV replication and antigen production (covalently closed circular DNA [cccDNA] and integrated HBV DNA), the high viral burden (HBV DNA and HBsAg) and the impaired host innate and adaptive immune responses against HBV. Current HBV therapeutics, 1 year of pegylated-interferon-α (PEG-IFNα) and long-term nucleos(t)ide analogues (NUCs), rarely achieve HBV cure. Stopping NUC therapy may lead to functional cure in some Caucasian patients but rarely in Asian patients. Switching from a NUC to IFN after HBV DNA suppression increases the chance of HBsAg clearance mainly in those with low HBsAg levels. Novel antiviral strategies that inhibit viral entry, translation and secretion of HBsAg, modulate capsid assembly, or target cccDNA transcription/degradation have shown promise in clinical trials. Novel immunomodulatory approaches including checkpoint inhibitors, metabolic modulation of T cells, therapeutic vaccines, adoptive transfer of genetically engineered T cells, and stimulation of innate and B-cell immune responses are being explored. These novel approaches may be further combined with NUCs or PEG-IFNα in personalised strategies, according to virologic and disease characteristics, to maximise the chance of HBV cure. The development of curative HBV therapies should be coupled with the development of standardised and validated virologic and immunologic assays to confirm target engagement and to assess response. In addition to efficacy, curative therapies must be safe and affordable to meet the goal of global elimination of hepatitis B.


Assuntos
Hepatite B Crônica , Hepatite B , Antivirais/uso terapêutico , DNA Circular , DNA Viral , Desenvolvimento de Medicamentos , Hepatite B/tratamento farmacológico , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Humanos , Interferon-alfa/uso terapêutico
16.
Front Immunol ; 13: 850404, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35634316

RESUMO

Saccharomyces cerevisiae is a commensal yeast colonizer of mucosal surfaces and an emerging opportunistic pathogen in the mucosa and bloodstream. The role of S. cerevisiae has been largely characterized in peripheral blood mononuclear cells and monocyte-derived dendritic cells, where yeast cells induce the production of inflammatory cytokines through the interaction with mannose receptors, chitin receptors, DC SIGN, and dectin1. However, the response of blood-circulating dendritic cells (DCs) to S. cerevisiae has never been investigated. Among blood DCs, conventional DCs (cDCs) are producers of inflammatory cytokines, while plasmacytoid DCs (pDCs) are a specialized population producing a large amount of interferon (IFN)-α, which is involved in the antiviral immune response. Here we report that both human DC subsets are able to sense S. cerevisiae. In particular, cDCs produce interleukin (IL)-6, express activation markers, and promotes T helper 17 cell polarization in response to yeasts, behaving similarly to monocyte-derived DCs as previously described. Interestingly, pDCs, not cDCs, sense fungal nucleic acids, leading to the generation of P1-pDCs (PD-L1+CD80-), a pDC subset characterized by the production of IFN-α and the induction of a Th profile producing IL-10. These results highlight a novel role of pDCs in response to S. cerevisiae that could be important for the regulation of the host microbiota-immune system balance and of anti-fungal immune response.


Assuntos
Células Dendríticas , Saccharomyces cerevisiae , Citocinas/metabolismo , Células Dendríticas/classificação , Células Dendríticas/microbiologia , Humanos , Interferon-alfa/metabolismo , Interleucina-6/metabolismo
17.
Front Immunol ; 13: 864354, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529845

RESUMO

Purpose: Our recent study showed a high rate of HBsAg clearance in inactive HBsAg carriers (IHCs) treated with pegylated IFN (PEG-IFN). To better understand the immune-mediated component of HBsAg clearance, this study investigated the role of serum immunoglobulin G (IgG) and its subclasses in predicting HBsAg clearance in IHCs with PEG-IFN therapy. Methods: In this study, IHCs received PEG-IFN for 96 weeks. Subjects who achieved clearance of HBsAg were considered responders (R group), and those in whom HBsAg was not cleared were considered non-responders (NR group). The HBsAg, ALT, and serum lgG subtypes (lgG1, IgG2, IgG3, lgG4) were tested at baseline, and at 12 and 24 weeks of treatment. To evaluate the factors in predicting HBsAg clearance, univariate and multivariate logistic regression analyses were performed. The receiver operator characteristic curves and the area under the receiver operator characteristic curve (AUROC) were used to evaluate prognostic values. Results: Our results showed that 39 cases obtained HBsAg clearance (group R), while 21 cases did not (group NR). There was no significant difference in age, ALT, and AST levels between the two groups. The serum levels of IgG1, lgG2, lgG3 and lgG4 at baseline, and at 12 and 24 weeks were significantly lower in IHC with HBsAg clearance than in the NR group. Univariate logistic regression analysis showed that serum IgG1, IgG2, IgG3, and IgG4 levels at baseline, and at 12, and 24 weeks were all strong predictors of HBsAg clearance. In all indicators, lgG2 had the highest AUROC at baseline and lgG3 the highest AUROC at week 12. A multifactor logistic analysis was performed with y=33.933-0.001*BaselinelgG1-0.002*BaselinelgG2. The area under the curve was 0.941 with 100% sensitivity and 76.19% specificity. Conclusion: Together, our findings suggest that serum IgG has a higher predictive value compared to the convention predictors of HBsAg and ALT for HBsAg clearance and thus may be a better clinical predictor of HBsAg clearance in IHCs.


Assuntos
Antígenos de Superfície da Hepatite B , Interferon-alfa , Antígenos de Superfície , Antivirais/uso terapêutico , Vírus da Hepatite B , Humanos , Imunoglobulina G/uso terapêutico , Interferon-alfa/uso terapêutico , Polietilenoglicóis/uso terapêutico
19.
PLoS Comput Biol ; 18(4): e1010053, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35468127

RESUMO

In HIV-1-infected individuals, transmitted/founder (TF) virus contributes to establish new infection and expands during the acute phase of infection, while chronic control (CC) virus emerges during the chronic phase of infection. TF viruses are more resistant to interferon-alpha (IFN-α)-mediated antiviral effects than CC virus, however, its virological relevance in infected individuals remains unclear. Here we perform an experimental-mathematical investigation and reveal that IFN-α strongly inhibits cell-to-cell infection by CC virus but only weakly affects that by TF virus. Surprisingly, IFN-α enhances cell-free infection of HIV-1, particularly that of CC virus, in a virus-cell density-dependent manner. We further demonstrate that LY6E, an IFN-stimulated gene, can contribute to the density-dependent enhancement of cell-free HIV-1 infection. Altogether, our findings suggest that the major difference between TF and CC viruses can be explained by their resistance to IFN-α-mediated inhibition of cell-to-cell infection and their sensitivity to IFN-α-mediated enhancement of cell-free infection.


Assuntos
Infecções por HIV , HIV-1 , Antivirais , Infecções por HIV/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia
20.
J Med Life ; 15(2): 269-277, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35419098

RESUMO

Cisplatin is well known as a potent anti-cancer agent against colon cancer. However, alpha interferons are also widely used for cancer suppression. This in vitro study was designed to investigate and compare the cancer suppression function of alpha interferon in colon cancer with Cisplatin. The analysis used a human SW 480 cancer cell line with RPMI-1630 culture media. Six dilutions of interferon (2.5 µg/ml, 1.25 µg/ml, 0.562 µg/ml, 0.286 µg/ml, 0.143 µg/ml, and 0.057 µg/ml) and six dilutions of cisplatin (100 µg/ml, 50 µg/ml, 25 µg/ml, 6.25 µg/ml, and 3.125) were used at 24, 48 and 72 hours along with the presence of control groups. Following this, results were observed by ELISA plate reader, and percentage inhibition was calculated using ANOVA analysis. The interferon and cisplatin percentage of inhibition was comparable with higher inhibition rates observed with alpha interferon. The statistical analysis showed that the maximum inhibition was observed at a 0.143 µg/ml interferon concentration when exposed for 48 to 72 hours. This in vitro analysis demonstrated the anti-cancer activity of alpha interferon and its advanced inhibitory activity compared to Cisplatin.


Assuntos
Cisplatino , Neoplasias do Colo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia
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