RESUMO
BACKGROUND: The impact of calcineurin inhibitors on achievement of sustained virological response to antiviral therapy for post-transplant recurrent hepatitis C is controversial. This study aimed at investigating the interactions between calcineurin inhibitors and interleukin-28B (IL-28B) gene polymorphisms and sustained virological response. METHODS: Retrospective study of 147 liver transplant recipients with recurrent hepatitis C, who received 48 weeks of peg-interferon-α (N=113) or standard interferon (N=34), in association with ribavirin. Cyclosporine and tacrolimus were administered in 68 and 79 patients, respectively. IL-28B rs12979860 allele frequency was assessed in both donors and recipients. RESULTS: Overall, 57 patients (38.8%) obtained sustained virological response; no difference was found between cyclosporine and tacrolimus-treated patients (42.6% vs. 35.4%, p=0.371). Recipient and donor IL-28B genotypic frequencies were C/C=30.6%, C/T=51.7%, T/T=17.7% and C/C=44.9%, C/T=50.3%, T/T=4.8%, respectively. Combining donor and recipient alleles, response rates decreased from cyclosporine-treated patients carrying ≤ 1 T allele (56.1%) to tacrolimus-treated patients carrying ≤ 1 T allele (44.7%) to patients carrying ≥ 2 T alleles (25.0%, p=0.0009). CONCLUSIONS: Donor and recipient rs12979860 alleles synergistically influence sustained virological response rate to antiviral treatment for recurrent hepatitis C. In patients carrying <2 T alleles cyclosporine favours a better response than tacrolimus, while no difference was found in the presence of ≥ 2 T alleles.
Assuntos
Inibidores de Calcineurina , DNA/genética , Hepatite C Crônica/terapia , Interferon-alfa/uso terapêutico , Interleucinas/genética , Transplante de Fígado/efeitos adversos , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Alelos , Antivirais/uso terapêutico , Quimioterapia Combinada , Seguimentos , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/etiologia , Hepatite C Crônica/genética , Interferons , Interleucinas/metabolismo , RNA Viral/genética , Proteínas Recombinantes/uso terapêutico , Recidiva , Estudos Retrospectivos , Ribavirina/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
We describe here the sequence and the molecular modeling of a new variant of HLA-A*32 allele officially named A*32:22. This novel allele has been detected in an Italian cord blood sample by sequence-based typing (SBT). The mutation (CAT âCGT), which has occurred at codon 151, at nucleotide position 524, implies an amino acidic change from Histidine to Arginine. Residue 151 is located on top of the molecule inside the region contacted by T cell receptor (TCR) and it is possibly involved in docking TCR. A positively charged residue is maintained on this position determining a slight change of electrostatic potential on the molecular surface. This suggests a limited functional relevance of the amino acid substitution encoded by A*32:22.
Assuntos
Antígenos HLA-A/genética , Modelos Moleculares , Alelos , Substituição de Aminoácidos , Sequência de Bases , Sangue Fetal/imunologia , Feto , Antígenos HLA-A/imunologia , Humanos , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , Análise de Sequência de DNA , Eletricidade Estática , Homologia Estrutural de ProteínaRESUMO
We describe here the sequences of 3 new HLA-DRB1 variants officially named DRB1*03:05:03, DRB1*11:10:02, and DRB1*14:86. These novel alleles have been detected in 3 Caucasoid individuals by sequence-based typing. The first and second alleles are the result of a silent mutation, which does not imply any amino acid change. The sequence of DRB1*14:86 exhibits a single nucleotide difference with the allele DRB1*14:01:01 at position 239.
Assuntos
Técnicas de Genotipagem/métodos , Cadeias HLA-DRB1/genética , Análise de Sequência de DNA/métodos , Alelos , Sequência de Bases , Humanos , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase , Polimorfismo Genético , Homologia de Sequência do Ácido Nucleico , População Branca/genéticaRESUMO
The innate immune system is present throughout the female reproductive tract and functions in synchrony with the adaptive immune system to provide protection in a way that enhances the chances for fetal survival, while protecting against potential pathogens. Recent data show that activation of Toll-like receptor (TLR)2 and 4 by low-molecular weight hyaluronic acid (LMW-HA) in the epidermis induces secretion of the antimicrobial peptide ß-defensin 2. In the present work, we show that LMW-HA induces vaginal epithelial cells to release different antimicrobial peptides, via activation of TLR2 and TLR4. Further, we found that LMW-HA favors repair of vaginal epithelial injury, involving TLR2 and TLR4, and independently from its classical receptor CD44. This wound-healing activity of LMW-HA is dependent from an Akt/phosphatidylinositol 3 kinase pathway. Therefore, these findings suggest that the vaginal epithelium is more than a simple physical barrier to protect against invading pathogens: on the contrary, this surface acts as efficient player of innate host defense, which may modulate its antimicrobial properties and injury restitution activity, following LMW-HA stimulation; this activity may furnish an additional protective activity to this body compartment, highly and constantly exposed to microbiota, ameliorating the self-defense of the vaginal epithelium in both basal and pathological conditions.
Assuntos
Adjuvantes Imunológicos/farmacologia , Epitélio/efeitos dos fármacos , Ácido Hialurônico/farmacologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Vagina/efeitos dos fármacos , Vagina/imunologia , Linhagem Celular Transformada , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Epitélio/imunologia , Epitélio/metabolismo , Feminino , Regulação da Expressão Gênica em Archaea/efeitos dos fármacos , Humanos , Ácido Hialurônico/metabolismo , Imunidade Inata , Fatores Imunológicos/imunologia , Fatores Imunológicos/metabolismo , Mediadores da Inflamação/metabolismo , Ligantes , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Cicatrização/genética , beta-Defensinas/genética , beta-Defensinas/metabolismoRESUMO
Many inflammatory diseases are characterized by an imbalance among lymphocyte populations, in particular Th1, Th2 and the recently described Th17 cells. The Th1/Th2 imbalance is linked to many factors, but certainly the role of cytokines is essential. In Th2 diseases IL-4 expression is predominant, while Th1 pathologies are characterized by high expression of IFN-gamma and IL-12. Though today the therapeutical proposal for many inflammatory diseases aims to re-establish normal levels of Th1/Th2 cytokines, the pharmacological use of cytokines, which are very active molecules, is limited by the possible collateral effects. Therefore, our study aims to determine, in a murine model of allergic asthma, the possible therapeutic activity of low dose cytokines solutions, mechanically activated. We found that oral administration of low doses IL-12 plus IFN-gamma is able to solve the bronchial hyperresponsiveness condition of mice, establishing normal cytokine levels. The anti-asthma activity was confirmed by histological analysis of lungs and broncho-alveolar lavage fluid cell count. Serum ovalbumin-specific IgE was also significantly inhibited by treatment with low dose activated cytokines solution. These findings may suggest a novel approach to diseases which involve a Th1/Th2 imbalance.