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
38 resultados
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- IgG from atopic individuals can mediate non-atopic infant thymic and adult peripheral CD8(+) TC2 skewing without influence on TC17 or TC22 cells(2021) SOUSA, T. R. de; SGNOTTO, F. Da Ressureicao; FAGUNDES, B. Oliveira; SANTOS, L. Souza; DUARTE, A. J. Da Silva; VICTOR, J. R.The potential of IgG antibodies as allergy regulators has been discussed for decades and was brought to light that anti-allergen IgG is related to allergy inhibition in children during the first years of life and that IgG repertoire can differ between atopic and non-atopic individuals. Here, we aimed to evaluate in vitro the differential effects of purified IgG from atopic and non-atopic individuals on the production of IL-4, IL-17, and IL-22 by human intra-thymic and mature peripheral CD8(+) T cells respectively termed as TC2, TC17, and TC22 cells. We additionally evaluated the IFN-gamma production by CD8(+) T cells. Thereupon we used infants thymic tissues from non-atopic mothers and blood samples from individuals clinically classified as non-atopic. Thymocytes or PBMCs were cultured with IgG from atopic or non-atopic individuals. As controls, we used commercial IgG (Intravenous immunoglobulin IVIg) or mock condition. The phenotype and intracellular cytokine production were evaluated using flow cytometry. IgG from atopic individuals could increase the frequency of TC2 cells in non-atopic infant thymic and adult peripheral cell cultures compared to all control conditions. Due to the TC2 cell's potential to collaborate with pathology and severity of asthma in humans, this evidence can cooperate with the understanding of the development of an atopic state.
- IgG from Adult Atopic Dermatitis (AD) Patients Induces Nonatopic Neonatal Thymic Gamma-Delta T Cells (gamma delta T) to Acquire IL-22/IL-17 Secretion Profile with Skin-Homing Properties and Epigenetic Implications Mediated by miRNA(2022) FAGUNDES, Beatriz Oliveira; SOUSA, Thamires Rodrigues de; NASCIMENTO, Andrezza; FERNANDES, Lorena Abreu; SGNOTTO, Fabio da Ressureicao; ORFALI, Raquel Leao; AOKI, Valeria; DUARTE, Alberto Jose da Silva; SANABANI, Sabri Saeed; VICTOR, Jefferson Russogamma delta T cells mature in the human thymus, and mainly produce IL-17A or IFN-gamma, but can also produce IL-22 and modulate a variety of immune responses. Here, we aimed to evaluate whether IgG from AD patients (AD IgG) can functionally modulate thymic nonatopic gamma delta T cells. Thymic tissues were obtained from 12 infants who had not had an atopic history. Thymocytes were cultured in mock condition, or in the presence of either AD IgG or therapeutic intravenous IgG (IVIg). Following these treatments, intracellular cytokine production, phenotype, and microRNA expression profiles were investigated. AD IgG could downregulate alpha 4 beta 7, upregulate CLA, and induce the production of IFN-gamma, IL-17, and IL-22 in gamma delta T cells. Although both AD IgG and IVIg could directly interact with gamma delta T cell membranes, AD IgG could reduce gamma delta T cell apoptosis. AD IgG could upregulate nine miRNAs compared to IVIg, and six when compared to the mock condition. In parallel, some miRNAs were downregulated. Target gene prediction and functional analysis indicated that some target genes were enriched in the negative regulation of cellular transcription. This study shows that AD IgG influences the production of IL-17 and IL-22 by intrathymic nonatopic gamma delta T cells, and demonstrates epigenetic implications mediated by miRNAs.
- Mechanism underlying polyvalent IgG-induced regulatory T cell activation and its clinical application: Anti-idiotypic regulatory T cell theory for immune tolerance(2023) VICTOR, Jefferson Russo; NAHM, Dong-HoThe regulatory T (Treg) cells constitute a functionally defined subpopulation of T cells that modulate the immune system and maintain immune tolerance through suppression of the development of autoimmune responses to self-antigens and allergic reactions to external antigens. Reduction in the number or function of Treg cells has been suggested as a key immune abnormality underlying the development of autoimmune and allergic diseases. In vitro studies have demonstrated that purified polyvalent immunoglobulin G (IgG) from multiple healthy blood donors can exert immunomodulatory effects on Treg cells. Incubation of polyvalent human IgG with purified CD4+CD25high T cells increased the intracellular expression of interleukin (IL)-10. Intravenous administration of polyvalent human IgG induced significant expansions of CD4+ Foxp3+ Treg cells and clinical improvements in patients with autoimmune diseases. In human clinical trials, intramuscular administration of autologous total IgG significantly increased the percentage of IL-10-producing CD4+ Treg cells in the peripheral blood of healthy subjects and provided significant clinical improvements in patients with atopic dermatitis. These results suggest a clinical usefulness of polyvalent IgG-induced activation of Treg cells in human subjects. This review proposes a new hypothesis for immune tolerance mechanism by integrating the pre-existing ""idiotypic network theory"" and ""Treg cell theory"" into an ""anti-idiotypic Treg cell theory."" Based on this hypothesis, an ""active anti-idiotypic therapy"" for allergic and autoimmune diseases using autologous polyvalent IgG (as immunizing antigens) is suggested as follows: (1) Intramuscular or subcutaneous administration of autologous polyvalent IgG produces numerous immunogenic peptides derived from idiotypes of autologous IgG through processing of dendritic cells, and these peptides activate anti-idiotypic Treg cells in the same subject. (2) Activated anti-idiotypic Treg cells secrete IL-10 and suppress Th2 cell response to allergens and autoimmune T cell response to self-antigens. (3) These events can induce a long-term clinical improvements in patients with allergic and autoimmune diseases. Further studies are needed to evaluate the detailed molecular mechanism underlying polyvalent IgG-induced Treg cell activation and the clinical usefulness of this immunomodulatory therapy for autoimmune and allergic diseases.
- The Potential of IgG to Induce Murine and Human Thymic Maturation of IL-10+B Cells (B10) Revealed in a Pilot Study(2020) INOUE, Amanda Harumi Sabo; LIRA, Aline Aparecida de Lima; DE-OLIVEIRA, Marilia Garcia; SOUSA, Thamires Rodrigues de; SGNOTTO, Fabio da Ressureicao; DUARTE, Alberto Jose da Silva; VICTOR, Jefferson RussoRegulatory B (B10) cells can control several inflammatory diseases, including allergies; however, the origin of peripheral B10 cells is not fully understood, and the involvement of primary lymphoid organs (PLOs) as a primary site of maturation is not known. Here, using a murine model of allergy inhibition mediated by maternal immunization with ovalbumin (OVA), we aimed to evaluate whether B10 cells can mature in the thymus and whether IgG can mediate this process. Female mice were immunized with OVA, and offspring thymus, bone marrow, spleen, lung, and serum samples were evaluated at different times and after passive transfer of purified IgG or thymocytes. A translational approach was implemented using human nonatopic thymus samples, nonatopic peripheral blood mononuclear cells (PBMCs), and IgG from atopic or nonatopic individuals. Based on the expression of CD1d on B cells during maturation stages, we suggest that B10 cells can also mature in the murine thymus. Murine thymic B10 cells can be induced in vitro and in vivo by IgG and be detected in the spleen and lungs in response to an allergen challenge. Like IgG from atopic individuals, human IgG from nonatopic individuals can induce B10 cells in the infant thymus and adult PBMCs. Our observations suggest that B10 cells may mature in the thymus and that this mechanism may be mediated by IgG in both humans and mice. These observations may support the future development of IgG-based immunoregulatory therapeutic strategies.
- Gamma-delta (gamma delta) T cell-derived cytokines (IL-4, IL-17, IFN-gamma and IL-10) and their possible implications for atopic dermatitis development(2023) FAGUNDES, Beatriz Oliveira; DE-SOUSA, Thamires Rodrigues; VICTOR, Jefferson RussoAtopic dermatitis (AD) is a chronic disease related to skin disorders that affect individuals in their childhood and can persist or start in adulthood. Patients affected by this disease commonly show skin lesions on the body surface (mainly on the upper and lower limbs) and allergic rhinitis or asthma crises. Looking at the disease from a molecular perspective, the major cytokines involved in inflammatory skin diseases, not only AD, include IL-4, IL-17, IFN-gamma and IL-10. Although they can produce these cytokines and infiltrate the affected epithelia in patients with AD, gamma delta T cells are still almost unexplored. In this update, we briefly discuss the involvement of IL-4, IL-17, IFN-gamma and IL-10 in the pathophysiology of AD and the possible role of gamma delta T cells during the inflammatory process.
- 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.
- IgG from atopic dermatitis patients induces non-atopic infant thymic invariant natural killer T (iNKT) cells to produce IL-4, IL-17, and IL-10(2020) SANTOS, Ludimila S.; SGNOTTO, Fabio da Ressureicao; SOUSA, Thamires R.; ORFALI, Raquel L.; AOKI, Valeria; DUARTE, Alberto Jose da Silva; VICTOR, Jefferson R.Background Atopic dermatitis (AD) pathogenesis still needs to be elucidated, but invariant natural killer T (iNKT) cell involvement was already described by several groups. Our group has demonstrated that IgG antibodies purified from AD patients can modulate cytokine production by thymic T cells. Here we aimed to investigate if IgG from AD patients can modulate infant non-atopic thymic iNKT cells cytokine production in order to collaborate with the elucidation of AD development in infancy. Methods Thymic tissues were obtained from children from non-atopic mothers, and IgG was purified from AD patients diagnosed as moderate or severe and, as controls, from subjects clinically classified as non-atopic individuals. PBMCs from non-atopic individuals were also used in this study. Results Our results demonstrated that IgG from AD patients could induce non-atopic children thymic iNKT cells to produce higher levels of intracellular IL-4, IL-10, and IL-17 when compared to all control conditions. No effect was observed in non-atopic adults peripheral iNKT. We also observed that IgG from AD patients induces an increase in the expression of CD4 and Ror gamma t transcription factor in non-atopic children thymic iNKT cells compared to the condition of all controls. Conclusions These observations suggest that IgG from AD patients can induce a cytokine profile by thymic iNKT cells from non-atopic infants compatible with the observations in AD development, which can collaborate with the elucidation of AD pathogenesis.
- 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.
conferenceObject PRECONCEPTIONAL IMMUNIZATION WITH OVA CAN INDUCE OFFSPRING IL-17 SECRETING B CELLS WITH REGULATORY POTENTIAL (B17): A POSSIBLE ROLE IN OFFSPRING ALLERGY INHIBITION.(2015) LIRA, A. A. L.; DE-OLIVEIRA, M. G.; DUARTE, A. J. S.; SATO, M. N.; VICTOR, J. R.conferenceObject IgG from atopic dermatitis patients induces IL-17 and IL-10 production in infant intra-thymic TCD4 and TCD8 cells(2018) SGNOTTO, F. R.; OLIVEIRA, M. G.; LIRA, A. A. L.; INOUE, A. H. S.; TITZ, T. O.; ORFALI, R. L.; BENTO-DE-SOUZA, L.; SATO, M. N.; AOKI, V.; DUARTE, A. J. S.; VICTOR, J. R.