JEFFERSON RUSSO VICTOR
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina
11 resultados
Resultados de Busca
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- Maternal immunization downregulates offspring TCD4 regulatory cells (Tregs) thymic maturation without implications for allergy inhibition(2018) OLIVEIRA, Marilia Garcia de; LIRA, Aline Aparecida de Lima; SGNOTTO, Fabio da Ressureicao; INOUE, Amanda Harumi Sabo; BELTRAME, Giovanna Rossi; SILVA, Debora da; MENGHINI, Ricardo Palamar; DUARTE, Alberto Jose da Silva; VICTOR, Jefferson RussoThe regulation of offspring allergy development mediated by maternal immunization was evidenced by several groups, and this mechanism seems to involve the induction of regulatory T cells (Tregs) on offspring. Here, we aimed to evaluate whether the effect of maternal immunization on offspring Tregs occurs as a result of peripheral or central modulation. Briefly, C57BL/6 female mice were immunized with OVA in Alum or Alum alone and boosted with OVA in saline or saline only after 10 and 20 days. Non-immunized offspring serum, thymus and spleen were evaluated at 3 or 20 days old, and some groups of pups were submitted to neonatal OVA-immunization protocol for the subsequent evaluation of antibody production and allergic response. Our experimental protocol could be validated because maternal OVA-immunization inhibited offspring allergic response as evidenced by the suppression of offspring IgE production and allergic lung inflammation. Interestingly, maternal immunization reduced the frequency of offspring thymic Tregs with an opposite effect on spleen Tregs. Furthermore, after neonatal immunization, the frequency of lung-infiltrated Tregs was also augmented on offspring from immunized mothers. In conclusion, maternal OVA-immunization can inhibit the thymic maturation of offspring Tregs without implications on peripheral Tregs induction and allergy inhibition.
- Tolerogenic microenvironment in neonatal period induced by maternal immunization with ovalbumin(2014) MUNIZ, Bruno Pacola; VICTOR, Jefferson Russo; OLIVEIRA, Luana de Mendonca; LIRA, Aline Aparecida de Lima; PERINI, Adenir; OLIVO, Clarice Rosa; ARANTES-COSTA, Fernanda Magalhaes; MARTINS, Milton Arruda; DUARTE, Alberto Jose da Silva; SATO, Maria NotomiMaternal immunization with allergens, such as ovalbumin (OVA), can inhibit the development of an allergic response in offspring. The regulatory mechanisms seem to be mediated by maternal antibodies (MatAbs) and factors generated by the maternal fetal interface. The aim of this study was to verify the pathways of inhibitory Ab transference after maternal immunization with OVA and the effect of the offspring's dendritic cells (DCs) on the generation of regulatory T (Treg) cells. We verified that preconceptional OVA immunization induces high levels of proinflammatory and regulatory cytokines in the amniotic fluid, allowing the transference of high levels of anti-OVA IgG1 Abs to the offspring. Using an adoptive nursing protocol, we verified that maternal immunization leads to MatAb transference by the placental route and by breastfeeding contribute to the inhibition of anaphylactic IgE and IgG1 Ab responses in immunized offspring. We observed that maternal immunization decreased eosinophil numbers in recovered bronchoalveolar lavage fluid and in the lung tissue, whereas with a lack of control of airway responsiveness to methacholine. Maternal immunization induced in young offspring a decreased percentage of CD11c+ DCs expressing MHC class II and CD40 molecules. Moreover, DCs from both groups of offspring when pulsed with OVA, were able to induce Treg cells in vitro. Similarly, OVA immunization at the neonatal stage increased the frequency of Treg cells, regardless of the mother's immunization status. These findings emphasize that maternal immunization leads to a complex interaction of regulatory factors, with MatAbs, DCs and Treg cells affecting the tolerance of offspring during an allergic response.
- Do different IgG repertoires play a role in B- and T-cell functional modulation during ontogeny? The ""hooks without bait"" theory(2020) VICTOR, Jefferson R.The mechanisms by which immunoglobulin (Ig)G can modulate immunity have been investigated over the past few decades. In the past three years, some studies have demonstrated that IgG can play a pivotal role in mediating complex interactions that result in functional lymphocyte modulation during maturation in self or offspring primary lymphoid organs. This effect appears to be dependent on the IgG repertoire in the absence of the influence of antigens and the functionality of diverse cell populations, including B, alpha beta T (CD4 T and CD8 T), invariant natural killer T and gamma delta T cells, in mice and humans. Based on the literature, especially on findings resulting from the therapeutic use of purified IgG (intravenous Ig) and recent pieces of evidence obtained by my group, the ""hooks without bait"" theory is described here to guide the future development of therapies for specific immune regulation.
- Preconceptional Immunization Can Modulate Offspring Intrathymic IL-17-Producing gamma delta T Cells with Epigenetic Implications Mediated by microRNAs(2021) DE-SOUSA, Thamires Rodrigues; PESSOA, Rodrigo; NASCIMENTO, Andrezza; FAGUNDES, Beatriz Oliveira; SGNOTTO, Fabio da Ressureicao; DUARTE, Alberto Jose da Silva; SANABANI, Sabri Saeed; VICTOR, Jefferson RussoThe mechanisms through which maternal immunization can modulate offspring thymic maturation of lymphocytes are not fully understood. Here, we aimed to evaluate whether maternal OVA-immunization can inhibit the maturation of IL-17-producing gamma delta T cells in offspring thymus, and if this mechanism has epigenetic implications mediated by microRNAs (miRNAs) expression. Wild-type (WT) C57BL/6 females were immunized with OVA in Alum or Alum alone and were mated with normal WT males. Evaluating their offspring thymus at 3 or 20 days old (d.o.), we observed that maternal OVA immunization could inhibit the thymic frequency of offspring CD27- and IL-17(+) gamma delta T cells at the neonatal and until 20 days old. Furthermore, we evaluated the expression of function-related gamma and delta variable gamma delta TCR chains (V gamma 1, V gamma 2, V gamma 3, V delta 4, and V delta 6.3), observing that maternal OVA-immunization inhibits V gamma 2 chains expression. The small RNAs (sRNAs), particularly miRNAs, and messenger RNAs (mRNA) expression profiles by pools of thymus tissue samples (from 9 to 11 mice) from offspring OVA-immunized or Alum-immunized mothers were analyzed via Illumina sequencing platform and bioinformatics approaches. Using a fold change >4, our results showed that seven miRNAs (mmu-miR-126a-3p, 101a-3p, 744-3p,142-5p, 15a-5p, 532-5p, and 98-5p) were differentially expressed between both groups. Ten target genes were predicted to interact with the seven selected miRNAs. There were no enriched categories of gene ontology functional annotation and pathway enrichment analysis for the target genes. Interestingly, four of the identified miRNAs (mmu-miR-15a, mmu-miR-101 mmu-miR-126, and mmu-miR-142) are related to IL-17 production. Our data is of significance because we demonstrate that maternal immunization can modulate offspring thymic maturation of IL-17-producing gamma delta T cells possibly by an epigenetic mechanism mediated by miRNAs.
- Influence of Maternal Immunization with Allergens on the Thymic Maturation of Lymphocytes with Regulatory Potential in Children: A Broad Field for Further Exploration(2014) VICTOR, Jefferson RussoA variety of mechanisms are involved in the regulation of offspring allergy development through maternal immunization with allergens. The passive transfer of antigens, antibodies, and cytokines, the induction of phenotypic alterations in offspring lymphocytes, and the induction of regulatory populations in offspring have been proposed, but these mechanisms remain incompletely understood. It is likely that maternal immunization could affect the intrathymic maturation of offspring TCD4+, TCD8+, gamma delta T, nTreg, iNKT, and B lymphocytes, although there are currently no human maternal immunization protocols for the regulation of allergic responses in children. Some studies have suggested a direct interaction between the maternal immune status and the offspring intrathymic microenvironment; this interaction could influence the maturation of offspring regulatory cells and must be explored for the development of therapies to control allergy development in children.
- Allergen-specific IgG as a mediator of allergy inhibition: Lessons from mother to child(2017) VICTOR, Jefferson RussoAllergen-specific IgG produced by immune mothers is associated with less predisposition to allergy development in their children. This finding has been described by several groups over the last few decades, but the mechanisms by which maternal IgG can inhibit allergy development are still not fully understood. With the purpose of summarizing past investigations, we review the literature on murine models of maternal immunization with allergens and on immune regulation in humans after passive therapy with purified IgG. Based on our review, a new hypothesis about these mechanisms is presented, which may provide a foundation for the future development of therapies to inhibit allergy development.
- Preconceptional allergen immunization can induce offspring IL-17 secreting B cells (B17): do they share similarities with regulatory B10 cells?(2018) LIRA, Aline Aparecida de Lima; DE-OLIVEIRA, Marilia Garcia; INOUE, Amanda Harumi Sabo; BELTRAME, Giovanna Rossi; DUARTE, Alberto Jose da Silva; VICTOR, Jefferson RussoBackground: IL-17-producing B cells can be identified in both mice and human and were named B17 cells. The role of B17 cells still needs to be elucidated and its inflammatory or regulatory functions remain controversial. Objective: We evaluate the effect of maternal immunization with OVA on offspring B cells that produces IL-17 and can show a regulatory potential by IL-10 production. Methods: C57BL/6 WT, IL-10(-/-) or CD28(-/-) female mice were immunized or not with OVA in Alum, and immunized females were boosted after 10 and 20 days. Immunized and non immunized females were mated, and pups from both groups were evaluated at 3 or 20 days old (d.o.). Some offspring from the aforementioned two groups were immunized with OVA at 3 d.o., boosted after 10 days and evaluated at 20 d.o. Results: Maternal immunization with OVA induced offspring B cells to produce IL-17 at higher intensity compared to the control group of offspring at 3 d.o. This effect was maintained until 20 d.o. and even after neonatal immunization with OVA. The co-production of IL-10 on offspring IL-17 + B cells is up-regulated in response to maternal immunization with OVA. Maternal immunization with OVA on IL-10(-/-)mice reveals reduced percentage and mean of fluorescence intensity of IL-17 on B cells of offspring. Conclusion: Preconception OVA immunization can induce offspring B cells that produce IL-17 at higher intensity and co-produce mainly IL-10. This could be the reason why B17 cells had been described in the literature with controversial roles upon their regulatory function.
- Preconception allergen sensitization can induce B10 cells in offspring: a potential main role for maternal IgG(2017) OLIVEIRA, Marlia Garcia de; OLIVEIRA, Luana de Mendonca; LIRA, Aline Aparecida de Lima; SGNOTTO, Fabio da Ressureicao; DUARTE, Alberto Jose da Silva; SATO, Maria Notomi; VICTOR, Jefferson RussoBackground: The mechanisms through which allergies can be inhibited after preconception immunization with allergens are not fully understood. We aimed to evaluate whether maternal immunization can induce a regulatory B (B10) cell population in offspring in concert with allergy inhibition. Methods: C57BL/6 females were or were not immunized with OVA and were mated with normal WT males. Their offspring were evaluated at 3 days of age or 20 days after neonatal immunization. Human peripheral B cells from atopic and non-atopic individuals were also evaluated. Results: Preconception OVA immunization induced B10 cells in offspring, and IL-10 production appeared to be critical for FcyRIIB upregulation in offspring B cells. Murine and human IL-10-producing B cells responded in vitro to IgG according to the atopic repertoire of the cells. Conclusions: Our results reveal that maternal immunization induces allergen-specific B10 cells in offspring and a pivotal role for the IgG repertoire in IL-10 production by murine and human B cells.
- Maternal IgG impairs the maturation of offspring intrathymic IL-17-producing gamma delta T cells: Implications for murine and human allergies(2019) DE-OLIVEIRA, Marilia G.; LIRA, Aline A. L.; SGNOTTO, Fabio R.; INOUE, Amanda H. S.; SANTOS, Ludimila S.; NAKAMATSU, Bernardo Y.; DUARTE, Alberto J. S.; LEITE-DE-MORAES, Maria; VICTOR, Jefferson R.Background The precise mechanism involved in the acquisition of the IL-17+ profile of gamma delta T cells, the ligands responsible for this change, and whether this default is acquired during intrathymic maturation need to be elucidated. Objective This study aimed to evaluate whether IL-17-producing gamma delta T cells are present in the airways of tolerant offspring from allergen-sensitized mothers and the possible implication of maternal IgG in the generation of these cells. Methods Female mice were immunized or not, and the allergic response, frequency of gamma delta T cell subsets and cytokine production of the offspring were analysed by flow cytometry. The effects of passive in vivo transfer of purified IgG were investigated in offspring. A translational approach was employed to analyse gamma delta T cells in the thymus and PBMCs from humans. Results Maternal immunization reduced the frequency of spontaneous IL-17-producing gamma delta T cells in the thymus, spleen and lung of offspring. This effect was mimicked by the in vivo treatment of females with purified IgG. IgG directly interacted with gamma delta T cell membranes. The modulatory effect of human IgG on human infant intrathymic and adult peripheral gamma delta T cells showed similarities to murine gamma delta T cells, which is rarely reported in the literature. Conclusions & Clinical Relevance Together, our results reveal that IgG from potentially tolerant atopic mothers can influence offspring thymic IL-17-producing gamma delta T cell maturation. Furthermore, we suggest that IgG is an unprecedented modulatory factor of murine and human gamma delta T cells. These observations may support the future development of IgG-based immunoregulatory therapeutic strategies.
- IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intrathymic TCD4 and TCD8 cells(2018) SGNOTTO, Fabio D. R.; OLIVEIRA, Marilia G. de; LIRA, Aline A. L.; INOUE, Amanda H. S.; TITZ, Tiago O.; ORFALI, Raquel L.; BENTO-DE-SOUZA, Luciana; SATO, Maria N.; AOKI, Valeria; DUARTE, Alberto J. S.; VICTOR, Jefferson R.IntroductionOur group recently demonstrated that IgG modulates T cell cytokine production during the maturation process in the human thymus. The effects of this modulation are IgG repertoire dependent and can exert a systemic and long-term impact. ObjectiveTo investigate whether IgG from atopic dermatitis (AD) patients can modulate cytokine production of infant intrathymic TCD4 and TCD8 cells in vitro. MethodsThymic tissues were obtained from newborn children from nonatopic mothers, and thymocytes were cultured for 6 days with purified IgG from AD patients or with intravenous immunoglobulin (IVIG) or mock conditions as controls. Cells were gated as double positive T cells (TDP(-)CD4(+)CD8(+)), TCD4 cells (CD4(+)CD8(-)), or TCD8 cells (CD4(-)CD8(+)), and intracellular levels of IL-17A, IFN-, TNF-, IL-4, IL-10, and TGF- were evaluated by flow cytometry. ResultsCompared to mock and IVIG culture conditions, IgG of AD individuals induced in vitro intracellular production of IL-17 and IL-10 by intrathymic TDP, TCD4, and TCD8 cells of infants. TGF- was also detected at a higher frequency in response to AD IgG in TDP and TCD8 cells compared to mock and IVIG cultured conditions. An opposite effect was detected upon IFN- production in TCD4 cells, such that AD IgG reduced IFN- production compared to production under mock conditions but not under IVIG conditions. ConclusionIgG of AD patients can stimulate cytokine production in infant thymocytes and thus resembles the peripheral profile observed in adults. These findings suggest a novel mechanism that can contribute to AD pathogenesis.