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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. Source

Mendonca V.R.,Federal University of Bahia | Lopes F.M.,University of Sao Paulo | Lopes F.M.,Federal Technological University of Parana | 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. Source

Amarante-Mendes G.P.,University of Sao Paulo | Amarante-Mendes G.P.,Institute Investigacao em Imunologia | Griffith T.S.,University of Minnesota
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. Source

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. Source

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. Source

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