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LIM/56 - Laboratório de Investigação em Dermatologia e Imunodeficiências, Hospital das Clínicas, Faculdade de Medicina

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Agora exibindo 1 - 10 de 14
  • article 3 Citação(ões) na Scopus
    Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial
    (2022) BAPTISTA, Marcella Vassao de Almeida; SILVA, Lais Teodoro da; SAMER, Sadia; OSHIRO, Telma Miyuki; SHYTAJ, Iart Luca; GIRON, Leila B.; PENA, Nathalia Mantovani; CRUZ, Nicolly; GOSUEN, Gisele Cristina; FERREIRA, Paulo Roberto Abrao; CUNHA-NETO, Edecio; GALINSKAS, Juliana; DIAS, Danilo; SUCUPIRA, Maria Cecilia Araripe; ALMEIDA-NETO, Cesar de; SALOMAO, Reinaldo; DUARTE, Alberto Jose da Silva; JANINI, Luis Mario; HUNTER, James R.; SAVARINO, Andrea; JULIANO, Maria Aparecida; DIAZ, Ricardo Sobhie
    Background: We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods: PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-alpha and GM-CSF. After sequencing each patient's HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients' cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-gamma) production were measured in CD4(+) and CD8(+)T-cells. Results: The protocol of ex-vivo treatment with IFN-a and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4(+) and CD8(+)T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-gamma expression was significantly increased in CD4(+) T-cells. The number of candidates that increased in vitro the cytokine levels in CD4(+) and CD8(+)T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions: MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment.
  • article 7 Citação(ões) na Scopus
    Host genetics contributes to the effectiveness of dendritic cell-based HIV immunotherapy
    (2018) REIS, Edione C.; SILVA, Lais T. da; SILVA, Wanessa C. da; RIOS, Alexandre; DUARTE, Alberto J.; OSHIRO, Telma M.; CROVELLA, Sergio; PONTILLO, Alessandra
    Systems biological analysis has recently revealed how innate immune variants as well as gut microbiota impact the individual response to immunization. HIV-infected (HIV+) patients have a worse response rate after standard vaccinations, possibly due to the immune exhaustion, increased gut permeability and microbial translocation. In the last decade, dendritic cells (DC)-based immunotherapy has been proposed as an alternative approach to control HIV plasma viral load, however clinical trials showed a heterogeneity of immunization response. Hypothesizing that host genetics may importantly affects the outcome of immunotherapy in HIV+ patients, genetic polymorphisms' distribution and gene expression modulation were analyzed in a phase I/II clinical trial of DC-based immunotherapy according to immunization response, and quality of vaccine product (DC). Polymorphisms in genes previously associated with progression of HIV infection to AIDS (i.e.: PARD3B, CCL5) contribute to a better response to immunotherapy in HIV+ individuals, possibly through a systemic effect on host immune system, but also directly on vaccine product. Genes expression profile after immunization correlates with different degrees of immune chronic activation/exhaustion of HIV+ patients (i.e. PD1, IL7RA, EOMES), but also with anti-viral response and DC quality (i.e.: APOBEC3G, IL8, PPIA), suggested that an immunocompetent individual would have a better vaccine response. These findings showed once more that host genetics can affect the response to DC-based immunotherapy in HIV+ individuals, contributing to the heterogeneity of response observed in concluded trials; and it can be used as predictor of immunization success.
  • article 2 Citação(ões) na Scopus
    Characterization of monocyte-derived dendritic cells used in immunotherapy for HIV-1-infected individuals
    (2018) SILVA, Lais Teodoro da; SILVA, Wanessa Cardoso da; ALMEIDA, Alexandre de; REIS, Denise da Silva; SANTLLO, Bruna Tereso; RIGATO, Paula Ordonhez; DUARTE, Alberto Jose da Silva; OSHIRO, Telma Miyuki
    Aims: A therapeutic vaccine based on monocyte-derived dendritic cells (MDDCs) has been shown to represent a promising strategy for the treatment of cancer and viral infections. Here, we characterized the MDDCs used as an immunogen in a clinical trial for an anti-HIV-1 therapeutic vaccine. Patients & Methods: Monocytes obtained from 17 HIV-infected individuals were differentiated into MDDCs and, after loading with autologous HIV, the cells were characterized concerning surface molecule expression, migratory and phagocytosis capacity, cytokine production and the induction of an effective cell-mediated immune response. Results: The MDDCs were able to induce antigen-specific responses in autologous CD4+ and CD8+ T lymphocytes. Conclusions: Despite a large interindividual variability, the results suggested that MDDCs present the potential to promote immune responses in vaccinated patients.
  • article 4 Citação(ões) na Scopus
    Patient with agammaglobulinemia produces anti-SARS-CoV-2 reactive T-cells after CoronaVac vaccine
    (2022) OSHIRO, Telma Miyuki; SILVA, Lais Teodoro da; ORTEGA, Marina Mazzilli; PERAZZIO, Sandro Felix; DUARTE, Alberto Jose da Silva; CARNEIRO-SAMPAIO, Magda
  • conferenceObject
    Anti-SARS-CoV-2 reactive T cells in a XLA patient after CoronaVac vaccine
    (2022) SILVA, Lais Teodoro da; ORTEGA, Marina Mazzilli; PERAZZIO, Sandro Felix; OSHIRO, Telma Miyuki; DUARTE, Alberto Jose da Silva; CARNEIRO-SAMPAIO, Magda
  • article 13 Citação(ões) na Scopus
    Antagonistic role of IL-1 beta and NLRP3/IL-18 genetics in chronic HIV-1 infection
    (2019) REIS, Edione C.; LEAL, Vinicius N. C.; SILVA, Lais T. da; REIS, Marilia M. L. dos; ARGANARAZ, Enrique R.; OSHIRO, Telma M.; PONTILLO, Alessandra
    Host genetics affects both susceptibility and progression of HIV-1 infection. NLRP3 inflammasome provides a first-line defense in viral infections, and, accordingly, gain-of-function variants in NLRP3 have been associated with protection against HIV-1. Despite antiretroviral treatment (ART), HIV-infected patients continue to present systemic inflammation with a heterogeneous prognosis. As NLRP3 inflammasome is involved in several chronic diseases by amplifying ""sterile"" inflammation, its role in chronic phase of HIV infection has been postulated. Little is known about inflammasome genetics in HIV-infected patients and whether it may play a role in the different clinical outcomes. Therefore, we questioned whether NLRP3 inflammasome genetics could affect the clinical course of HIV-1 infection as it does in host/virus interaction. For this purpose, we analyzed selected single nucleotide polymorphisms (SNPs) in ART-treated HIV-infected patients (n = 300), in Long Term Non-Progressors/Elite Controllers and progressors (n = 133), and in HIV-infected individuals submitted to dendritic cell (DC)-based immunotherapy (n = 19). SNPs leading to increased activation of NLRP3 inflammasome are beneficial for patients, while SNPs that negatively affect NLRP3 activation or IL-18 production, detrimental. In contrast, gain-of-function variant in IL1B is also detrimental for patients, suggesting that while IL-1 beta possible contributes to immune exhaustion, the axis NLRP3-inflammasome/IL-18 could act positively in chronic infection. Functional assays supported genetic results: NLRP3 variants associated with good quality HIV + DC, and ILIB -511C > T with a poor one. Loss-of-function SNPs affect HIV + T cells proliferation. These findings proposed for the first time that NLRP3 inflammasome, mainly through IL-18, play a protective role in chronic HIV infection.
  • article 1 Citação(ões) na Scopus
    Autologous and allogenic systems of HIV expansion: what is the better choice for clinical application in therapeutic vaccine?
    (2013) SILVA, Lais Teodoro da; PONTILLO, Alessandra; SILVA, Wanessa Cardoso da; ALMEIDA, Alexandre de; DUARTE, Alberto Jose da Silva; OSHIRO, Telma Miyuki
    Aims: HIV-1 expanded in an allogenic system (Al-HIV) represents a cheaper and faster alternative to the autologous virus (Au-HIV) as an antigen in anti-HIV immunotherapy. In this study, chemically inactivated HIV-1 obtained through autologous or allogenic systems were compared. Patients & methods: Au-HIV and Al-HIV obtained from cultures of peripheral blood mononuclear cells from 11 HIV+ individuals were tested for virus production, yield and time of culture, and their ability to elicit a specific immune response in vitro. Results: The allogenic system was more efficient than the autologous system. Dendritic cells pulsed with Au-HIV and Al-HIV presented a similar phenotypic profile, but only Al-HIV induced a significant increase in IFN-(+) lymphocytes. Conclusion: The use of an allogenic system displays several advantages in terms of cell manipulation, time and cost of culture, and immunogenicity.
  • article 56 Citação(ões) na Scopus
    HIV-1 induces NALP3-inflammasome expression and interleukin-1 beta secretion in dendritic cells from healthy individuals but not from HIV-positive patients
    (2012) PONTILLO, Alessandra; SILVA, Lais T.; OSHIRO, Telma M.; FINAZZO, Claudia; CROVELLA, Sergio; DUARTE, Alberto J. S.
    Objective: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals. Design and methods: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1 beta (IL-1 beta) secretion. Results: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1b secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients' immune cells. Conclusion: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
  • article 4 Citação(ões) na Scopus
    Phenotypic and functional profile of IFN-alpha-differentiated dendritic cells (IFN-DCs) from HIV-infected individuals
    (2019) SANTILLO, Bruna Tereso; REIS, Denise da Silva; SILVA, Lais Teodoro da; ROMANI, Nathalia Teixeira; DUARTE, Alberto Jose da Silva; OSHIRO, Telma Miyuki
    Dendritic cell (DC)-based immunotherapy is a promising strategy for the treatment of HIV-infected individuals. Different from the conventional protocol for DC differentiation based on the cytokine IL-4 (IL4-DCs), several studies have suggested obtaining DCs by culturing monocytes with type I IFN (IFN-alpha) to yield IFN-DCs, as performed in cancer therapy. To evaluate the phenotypic and functional characteristics, monocytes from HIV-infected subjects were differentiated into IFN-DCs or IL4-DCs, pulsed with chemically inactivated HIV and stimulated with pro-inflammatory cytokines. A comparative analysis between both types of monocyte-derived DCs (MoDCs) showed that immature IFN-DCs were phenotypically distinct from immature IL4-DCs at the baseline of differentiation, presenting a pre-activated profile. From the functional profile, we determined that IFN-DCs were capable of producing the cytokine IL-12 p70 and of inducing the production of IFN-gamma by CD4 + T lymphocytes but not by TCD8+ lymphocytes. Our results suggest that IFN-DCs derived from HIV-infected individuals are able to recognize and present viral antigens to induce TCD4+ cellular immunity to HIV.
  • article 20 Citação(ões) na Scopus
    Using Dendritic Cell-Based Immunotherapy to Treat HIV: How Can This Strategy be Improved?
    (2018) SILVA, Lais Teodoro da; SANTILLO, Bruna Tereso; ALMEIDA, Alexandre de; DUARTE, Alberto Jose da Silva; OSHIRO, Telma Miyuki
    Harnessing dendritic cells (DC) to treat HIV infection is considered a key strategy to improve anti-HIV treatment and promote the discovery of functional or sterilizing cures. Although this strategy represents a promising approach, the results of currently published trials suggest that opportunities to optimize its performance still exist. In addition to the genetic and clinical characteristics of patients, the efficacy of DC-based immunotherapy depends on the quality of the vaccine product, which is composed of precursor-derived DC and an antigen for pulsing. Here, we focus on some factors that can interfere with vaccine production and should thus be considered to improve DC-based immunotherapy for HIV infection.