RESUMO
BACKGROUND: In recent years, there has been great interest in developing molecular adjuvants based on antisense oligonucleotides (ASOs) targeting immunosuppressor pathways with inhibitory effects on regulatory T cells (Tregs) to improve immunogenicity and vaccine efficacy. We aim to evaluate the immunostimulating effect of 2'OMe phosphorothioated Foxp3-targeted ASO in an antifungal adjuvanted recombinant vaccine. METHODS: The uptake kinetics of Foxp3 ASO, its cytotoxicity and its ability to deplete Tregs were evaluated in murine splenocytes in vitro. Groups of mice were vaccinated with recombinant enolase (Eno) of Sporothix schenckii in Montanide Gel 01 adjuvant alone or in combination with either 1 µg or 8 µg of Foxp3 ASO. The titers of antigen-specific antibody in serum samples from vaccinated mice (male C57BL/6) were determined by ELISA (enzyme-linked immunosorbent assay). Cultured splenocytes from each group were activated in vitro with Eno and the levels of IFN-γ and IL-12 were also measured by ELISA. The results showed that the anti-Eno antibody titer was significantly higher upon addition of 8 µM Foxp3 ASO in the vaccine formulation compared to the standard vaccine without ASO. In vitro and in vivo experiments suggest that Foxp3 ASO enhances specific immune responses by means of Treg depletion during vaccination. CONCLUSION: Foxp3 ASO significantly enhances immune responses against co-delivered adjuvanted recombinant Eno vaccine and it has the potential to improve vaccine immunogenicity.
Assuntos
Fatores de Transcrição Forkhead/genética , Inativação Gênica , Imunogenicidade da Vacina , Oligonucleotídeos Antissenso/química , Sporothrix/imunologia , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Farmacêuticos , Animais , Sistema Imunitário , Interferon gama/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Cinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Baço/citologia , Linfócitos T Reguladores/metabolismoRESUMO
: Antisense oligonucleotides (ASOs) are synthetically prepared short single-stranded deoxynucleotide sequences that have been validated as therapeutic agents and as a valuable tool in molecular driving biology. ASOs can block the expression of specific target genes via complementary hybridization to mRNA. Due to their high specificity and well-known mechanism of action, there has been a growing interest in using them for improving vaccine efficacy. Several studies have shown that ASOs can improve the efficacy of vaccines either by inducing antigen modification such as enhanced expression of immunogenic molecules or by targeting certain components of the host immune system to achieve the desired immune response. However, despite their extended use, some problems such as insufficient stability and low cellular delivery have not been sufficiently resolved to achieve effective and safe ASO-based vaccines. In this review, we analyze the molecular bases and the research that has been conducted to demonstrate the potential use of ASOs in vaccines.
Assuntos
Adjuvantes Imunológicos/farmacologia , Imunidade/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Adjuvantes Imunológicos/farmacocinética , Animais , Humanos , Oligonucleotídeos Antissenso/imunologia , Oligonucleotídeos Antissenso/farmacocinética , Vacinação , Vacinas/imunologia , Vacinas/farmacocinética , Vacinas/farmacologiaRESUMO
Aim: The influence of variants in pharmacokinetics-related genes on long-term exposure to tacrolimus (TAC)-based therapy and clinical outcomes was investigated. Patients & methods: Brazilian kidney recipients were treated with TAC combined with everolimus (n = 178) or mycophenolate sodium (n = 97). The variants in CYP2C8, CYP2J2, CYP3A4, CYP3A5, POR, ABCB1, ABCC2, ABCG2, SLCO1B1 and SLCO2B1 were analyzed. Main results:CYP3A5*3/*3 genotype influenced increase in TAC concentration from week 1 to month 6 post-transplantation (p < 0.05). The living donor and CYP2C8*3 variant were associated with reduced risk for delayed graft function (OR = 0.07; 95% CI = 0.03-0.18 and OR = 0.45; 95% CI = 0.20-0.99, respectively, p < 0.05). Conclusion: The CYP3A5*3 variant is associated with increased early exposure to TAC. Living donor and CYP2C8*3 variant seem to be protective factors for delayed graft function in kidney recipients.
Assuntos
Citocromo P-450 CYP2C8/genética , Citocromo P-450 CYP3A/genética , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Adulto , Brasil/epidemiologia , Feminino , Genótipo , Humanos , Terapia de Imunossupressão/métodos , Imunossupressores/administração & dosagem , Imunossupressores/imunologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/administração & dosagem , Tacrolimo/imunologia , Resultado do TratamentoRESUMO
Este artículo tiene por objetivo dibujar la situación de las mujeres inmigrantes en la Comunidad Autónoma del País Vasco (CAPV) en el ámbito laboral, tomando como referencia dos periodos temporales distintos, en 2010 cuando la crisis económica global comienza a acechar a la economía vasca, y en 2014 una vez avanzada y que permite valorar su impacto en este colectivo. Tal comparación nos permitirá analizar la evolución en el mercado laboral y la respuesta de estas mujeres, generalmente protagonistas de situaciones de mayor vulnerabilidad y discriminación.(AU)
This article aims to draw the situation of immigrant women in the labor market in the Basque Country. We study two different periods, 2010 when the global crisis appears in the basque economy, and 2014, when we can value the impact on this group. This comparison will allow us to analyze the evolution in the labor market and the response of these women, who have experienced situations of greater vulnerability and discrimination.(AU)