Institute Investigacao em Imunologia

Brazil

Institute Investigacao em Imunologia

Brazil
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Mendonca V.R.,Federal University of Bahia | Lopes F.M.,University of Sao Paulo | Lopes F.M.,Federal Technological University of Paraná | Andrade B.B.,National Institute of Allergy and Infectious Diseases | And 2 more authors.
Malaria Journal | Year: 2013

Background: Plasmodium vivax malaria clinical outcomes are a consequence of the interaction of multiple parasite, environmental and host factors. The host molecular and genetic determinants driving susceptibility to disease severity in this infection are largely unknown. Here, a network analysis of large-scale data from a significant number of individuals with different clinical presentations of P. vivax malaria was performed in an attempt to identify patterns of association between various candidate biomarkers and the clinical outcomes. Methods. A retrospective analysis of 530 individuals from the Brazilian Amazon, including P. vivax-infected individuals who developed different clinical outcomes (148 asymptomatic malaria, 187 symptomatic malaria, 13 severe non-lethal malaria, and six severe lethal malaria) as well as 176 non-infected controls, was performed. Plasma levels of liver transaminases, bilirubins, creatinine, fibrinogen, C-reactive protein, superoxide dismutase (SOD)-1, haem oxygenase (HO)-1 and a panel composed by multiple cytokines and chemokines were measured and compared between the different clinical groups using network analysis. Results: Non-infected individuals displayed several statistically significant interactions in the networks, including associations between the levels of IL-10 and IL-4 with the chemokine CXCL9. Individuals with asymptomatic malaria displayed multiple significant interactions involving IL-4. Subjects with mild or severe non-lethal malaria displayed substantial loss of interactions in the networks and TNF had significant associations more frequently with other parameters. Cases of lethal P. vivax malaria infection were associated with significant interactions between TNF ALT, HO-1 and SOD-1. Conclusions: The findings imply that clinical immunity to P. vivax malaria is associated with multiple significant interactions in the network, mostly involving IL-4, while lethality is linked to a systematic reduction of complexity of these interactions and to an increase in connections between markers linked to haemolysis-induced damage. © 2013 Mendonça et al; licensee BioMed Central Ltd.


Weinlich R.,University of Sao Paulo | Weinlich R.,Institute Investigacao em Imunologia | Mognol G.P.,Instituto Nacional Of Cancer | Robbs B.K.,Instituto Nacional Of Cancer | And 3 more authors.
Journal of Immunology | Year: 2010

Over the past 20 y, the hormone melatonin was found to be produced in extrapineal sites, including cells of the immune system. Despite the increasing data regarding the biological effects of melatonin on the regulation of the immune system, the effect of this molecule on T cell survival remains largely unknown. Activation-induced cell death plays a critical role in the maintenance of the homeostasis of the immune system by eliminating self-reactive or chronically stimulated T cells. Because activated T cells not only synthesize melatonin but also respond to it, we investigated whether melatonin could modulate activation-induced cell death. We found that melatonin protects human and murine CD4+ T cells from apoptosis by inhibiting CD95 ligand mRNA and protein upregulation in response to TCR/CD3 stimulation. This inhibition is a result of the interference with calmodulin/calcineurin activation of NFAT that prevents the translocation of NFAT to the nucleus. Accordingly, melatonin has no effect on T cells transfected with a constitutively active form of NFAT capable of migrating to the nucleus and transactivating target genes in the absence of calcineurin activity. Our results revealed a novel biochemical pathway that regulates the expression of CD95 ligand and potentially other downstream targets of NFAT activation. Copyright ©2010 by The American Association of Immunologists, Inc. All rights reserved.


De Oliveira C.I.,Institute Investigacao em Imunologia | Brodskyn C.I.,Institute Investigacao em Imunologia
Frontiers in Immunology | Year: 2012

Leishmaniases are a group of diseases caused by protozoa of the genus Leishmania that affect millions of people worldwide. These diseases are caused by distinct Leishmania species, of which L. braziliensis, a NewWorld representative of the Leishmania genus, has been the least studied. Although leishmaniasis caused by L. braziliensis induces a range of clinical manifestations ranging from mild localized lesions to severe mucosal involvement, few studies have focused on elucidating the immune mechanisms behind this pathology. In this review, we focus on the immunobiology of L. braziliensis infection, emphasizing the innate and adaptive immune responses and taking into consideration both studies performed inendemic are as and experimental models of infection. Additionally, weaddress recent findings regarding the role of sand fly saliva in disease immunopathogenesis and vaccine development. © 2012 de Oliveira and Brodskyn.


Anderson P.L.,University of Colorado at Denver | Glidden D.V.,University of California at San Francisco | Liu A.,HIV Research Section | Buchbinder S.,University of California at San Francisco | And 17 more authors.
Science Translational Medicine | Year: 2012

Drug concentrations associated with protection from HIV-1 acquisition have not been determined. We evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial (1). In this randomized placebo-controlled trial, daily oral doses of emtricitabine/tenofovir disoproxil fumarate were used as pre-exposure prophylaxis (PrEP) in men who have sex with men. Drug was detected less frequently in blood plasma and in viable cryopreserved peripheral blood mononuclear cells (PBMCs) in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% versus 44%; P < 0.001) and in the 90 days before that visit (11% versus 51%; P < 0.001). An intracellular concentration of the active form of tenofovir, tenofovir-diphosphate (TFV-DP), of 16 fmol per million PBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, the STRAND trial, yielded TFV-DP concentrations that, when analyzed according to the iPrEx model, corresponded to an HIV-1 risk reduction of 76% for two doses per week, 96% for four doses per week, and 99% for seven doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.


Papotto P.H.,Hospital Israelita Albert Einstein | Marengo E.B.,Hospital Israelita Albert Einstein | Sardinha L.R.,Hospital Israelita Albert Einstein | Goldberg A.C.,Hospital Israelita Albert Einstein | And 3 more authors.
Autoimmunity Reviews | Year: 2014

Autoimmune uveitis is an organ-specific disorder characterized by irreversible lesions to the eye that predominantly affect people in their most productive years and is among the leading causes of visual deficit and blindness. Currently available therapies are effective in the treatment of a wide spectrum of uveitis, but are often associated with severe side effects. Here, we review ongoing research with promising immunomodulatory therapeutic strategies, describing their specific features, interactions and the responses triggered by the targeted immune molecules that aim to minimize clinical complications and the likelihood of disease relapse. We first review the main features of the disease, diagnostic tools, and traditional forms of therapy, as well as the animal models predominantly used to understand the pathogenesis and test the novel intervention approaches aiming to control the acute immune and inflammatory responses and to dampen chronic responses. Both exploratory research and clinical trials have targeted either the blockade of effector pathways or of their companion co-stimulatory molecules. Examples of targets are T cell receptors (CD3), their co-stimulatory receptors (CD28, CTLA-4) and corresponding ligands (B7-1 and B7-2, also known as CD80 and CD86), and cytokines like IL-2 and their receptors. Here, we summarize the available evidence on effectiveness of these treatments in human and experimental uveitis and highlight a novel CD28 antagonist monovalent Fab' antibody, FR104, which has shown preclinical efficacy suppressing effector T cells while enhancing regulatory T cell function and immune tolerance in a humanized graft-versus-host disease (GVHD) mice model and is currently being tested in a mouse autoimmune uveitis model with encouraging results. © 2014.


de Carvalho D.D.,Ontario Cancer Institute | Mello B.P.,University of Sao Paulo | Pereira W.O.,University of Sao Paulo | Amarante-Mendes G.P.,University of Sao Paulo | Amarante-Mendes G.P.,Institute Investigacao em Imunologia
Current Molecular Medicine | Year: 2013

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exerts a cancer cell-specific pro-apoptotic activity.This property made the TRAIL associated pathway one of the most promising strategies aimed at inducing tumor-selective death.In fact, several approaches have been considered to explore this pathway for cancer therapy, such as recombinant TRAIL, agonist antibodies for TRAIL receptors, and adenoviral TRAIL.However, all of these approaches have certain disadvantages that limit their clinical use.Our recent discovery that the complex PRAME/EZH2 is able to repress TRAIL expression, in a cancer-specific manner, suggests an alternative approach for combined cancer therapy.A genetic or pharmacological inhibition of TRAIL repressors in cancer cells could restore endogenous TRAIL expression, thereby overcoming some of the limitations of and/or cooperating with previous approaches.© 2013 Bentham Science Publishers.


Lage S.L.,University of Sao Paulo | Amarante-Mendes G.P.,University of Sao Paulo | Amarante-Mendes G.P.,Institute Investigacao em Imunologia | Bortoluci K.R.,University of Sao Paulo | Bortoluci K.R.,Instituto Nacional Of Ciencia E Tecnologia Of Vacinas Inctv
Methods | Year: 2013

Pyroptosis is a molecularly controlled form of cell death that exhibits some features of apoptosis as well of necrosis. Pyroptosis is induced by inflammasome-activated caspase-1 or caspase-11 (caspase-4 in humans), as a result of distinct pathogenic or damage stimuli. Although pyroptosis displays some morphological and biochemical features of apoptosis, it has an inflammatory outcome due to the loss of plasma membrane integrity and the consequent release of intracellular contents, reminiscent to necrosis. Here, we use cytosolic delivery of purified flagellin as an experimental tool to trigger pyroptosis and describe potential methods to study this form of cell death. Finally, we discuss the advantages and limitations of these methods. © 2013 Elsevier Inc.


Weinlich R.,University of Sao Paulo | Weinlich R.,Institute Investigacao em Imunologia | Weinlich R.,St Jude Childrens Research Hospital | Brunner T.,University of Bern | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2010

The death receptor ligands are involved in many physiological and pathological processes involving triggering of apoptosis, inflammation, proliferation, and activation. The expression of these molecules is reported to be tightly regulated at the transcriptional level. However, over the last few years, an increasing number of data demonstrated that the control of transcription is only one of the mechanisms that manage the expression of the death receptor ligands. Thus, this review is focused on posttranslational regulation of the three main members of this family, namely FasL, TNF-α, and TRAIL. We discuss here the importance of distribution, storage, and degranulation of these molecules, as well as their shedding by proteases on the control of death receptor ligands expression and activity. © 2010 Springer Basel AG.


Amarante-Mendes G.P.,University of Sao Paulo | Amarante-Mendes G.P.,Institute Investigacao em Imunologia | Griffith T.S.,University of Minnesota | Griffith T.S.,Minneapolis VA Health Care System
Pharmacology and Therapeutics | Year: 2015

TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. © 2015 Elsevier Inc.


Coelho V.,University of Sao Paulo | Coelho V.,Institute Investigacao em Imunologia | Faria A.M.C.,Institute Investigacao em Imunologia | Faria A.M.C.,Federal University of Minas Gerais
Frontiers in Immunology | Year: 2012

Heat shock proteins 60 (HSP60) is one of the most well studied member of the HSP family. Although found to be a target self antigen in pathological autoimmunity and HSP60-reactive T and B cells are part of immune responses in several infectious diseases, there is consistent experimental evidence that HSP60 displays dominant immunoregulatory properties. There are a series of reports on animal models showing that the administration of HSP60 can modulate inflammatory diseases. However, HSP60 has both immune-regulatory and inflammatory properties placing it as an essentially homeostatic antigen, but with potentially harmful effects as well. There have been a series of reports on the successful use of HSP60 and its peptides as immune-modulatory agent for several models of autoimmune diseases and in some clinical trials as well. We believe that the potential risks of HSP60 as a therapeutic agent can be controlled by addressing important factors determining its effects.These factors would be route of administration, appropriate peptides, time point of administration in the course of the disease, and possible association with other modulatory agents.

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