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1.
Adv Ther ; 40(6): 2836-2854, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37129772

RESUMO

INTRODUCTION: The KEYNOTE-054 trial found that adjuvant treatment with pembrolizumab improved recurrence-free survival versus placebo in completely resected high-risk stage III melanoma patients. We assessed the cost-effectiveness of adjuvant pembrolizumab in Colombia compared with watchful waiting, a widely used strategy despite the high risk of recurrence with surgery alone. METHODS: A four-health state [recurrence-free (RF), locoregional recurrence (LR), distant metastases (DM), and death) Markov model was developed to assess the lifetime medical costs and outcomes (3% annual discount), along with cost-effectiveness ratios (ICERs). The transitions from the RF and LR states were modeled using KEYNOTE-054 data, and those from the DM state were modeled using data from the KEYNOTE-006 trial and a network meta-analysis of advanced treatments received after adjuvant pembrolizumab and watchful waiting. The health state utilities were derived from KEYNOTE-054 Euro-QoL data and literature. Costs are expressed in 2021 Colombian pesos (COP). RESULTS: Over a 46-year time horizon, patients on adjuvant pembrolizumab and watchful waiting were estimated to gain 9.69 and 7.56 quality-adjusted life-years (QALYs), 10.83 and 8.65 life-years (LYs), and incur costs of COP 663,595,726 and COP 563,237,206, respectively. The proportion of LYs spent in RF state was 84.63% for pembrolizumab and 72.13% for watchful waiting, yielding lower subsequent treatment, disease management, and terminal care costs for pembrolizumab. Adjuvant pembrolizumab improved survival by 2.18 LYs and 2.13 QALYs versus watchful waiting. The ICER per QALY was COP 47,081,917, primarily driven by recurrence rates and advanced melanoma treatments. The deterministic sensitivity analysis results were robust and consistent across various reasonable inputs and alternative scenarios. At a willingness-to-pay threshold of COP 69,150,201 per QALY, the probability of pembrolizumab being cost-effective was 65.70%. CONCLUSION: Pembrolizumab is cost-effective as an adjuvant treatment compared to watchful waiting among patients with high-risk stage III melanoma after complete resection in Colombia.


Assuntos
Melanoma , Qualidade de Vida , Humanos , Análise Custo-Benefício , Colômbia , Recidiva Local de Neoplasia/tratamento farmacológico , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Anos de Vida Ajustados por Qualidade de Vida , Adjuvantes Imunológicos/uso terapêutico , Linfonodos/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma Maligno Cutâneo
2.
Hematol., Transfus. Cell Ther. (Impr.) ; 41(3): 262-267, July-Sept. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1039932

RESUMO

ABSTRACT Introduction: Infection by Trypanosoma cruzi is challenging to blood bank supplies in terms of accurate diagnosis, mostly due to its clinical complexity. Infected individuals may remain asymptomatic for years, albeit they may have circulating parasites potentially transferable to eventual receptors of a transfusion. Objective: Although risk donors are systematically excluded through a survey, an important residual risk for transmission remains, evidencing the need to implement additional actions for the detection of T. cruzi in blood banks. Method: A review of the scientific literature is presented with the objective of identifying relevant publications on this subject. Results: We discuss the diagnostic considerations of this chronic infection on transfusion medicine and some recent advances in the processing of blood and derivatives units. Conclusion: Finally, recommendations are made on how the transmission of T. cruzi can be avoided through the implementation of better diagnostic and pathogen control measures at blood banks.


Assuntos
Trypanosoma cruzi , Bancos de Sangue , Fatores Epidemiológicos , Doença de Chagas/diagnóstico , Segurança do Sangue
3.
Hematol Transfus Cell Ther ; 41(3): 262-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085149

RESUMO

INTRODUCTION: Infection by Trypanosoma cruzi is challenging to blood bank supplies in terms of accurate diagnosis, mostly due to its clinical complexity. Infected individuals may remain asymptomatic for years, albeit they may have circulating parasites potentially transferable to eventual receptors of a transfusion. OBJECTIVE: Although risk donors are systematically excluded through a survey, an important residual risk for transmission remains, evidencing the need to implement additional actions for the detection of T. cruzi in blood banks. METHOD: A review of the scientific literature is presented with the objective of identifying relevant publications on this subject. RESULTS: We discuss the diagnostic considerations of this chronic infection on transfusion medicine and some recent advances in the processing of blood and derivatives units. CONCLUSION: Finally, recommendations are made on how the transmission of T. cruzi can be avoided through the implementation of better diagnostic and pathogen control measures at blood banks.

4.
Expert Rev Cardiovasc Ther ; 15(5): 367-376, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28388241

RESUMO

Introduction: Chagas disease (CD) is caused by a parasitic infection. The disease usually occurs after decades of the primary infection and can involve the myocardium or the digestive system. Of note, around 30% of T. cruzi infected patients develop CD while the other 70% may remain asymptomatic for their entire life. CD is usually observed as familial clustered phenomena. Moreover, individuals with chronic Chagas heart disease (CCHD) usually present a strong, deregulated immune response, which strongly suggests an immunogenetic effect.Areas covered: In this article we review and discuss the information currently available from the published scientific literature regarding the genetic variants of molecules of the immune system that contribute to the clinical presentation of the disease.Expert commentary: Of note, the most promissory results are found on the polymorphisms of chemokine receptors, particularly CCR5 and CCR2. Additional investigations are required, particularly with a focus on the genes that regulate the immune system.

5.
Bioessays ; 37(5): 474-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25731149

RESUMO

The recent explosion in the number of predatory journals has led to the appearance of questionable websites providing fake or spurious impact factors, which are analyzed and discussed here. We believe that academic associations, universities, and research funding bodies must take action to stop these questionable practices.


Assuntos
Bibliometria , Fator de Impacto de Revistas , Pesquisa Biomédica/normas
6.
Expert Rev Cardiovasc Ther ; 12(2): 187-200, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24450513

RESUMO

Infectious myocarditis (IM) is a commonly undiagnosed condition that may cause several heart diseases, including dilated cardiomyopathy and chronic heart failure. The understanding of the physiopathology of myocardial inflammation is crucial for a timely diagnosis and for the control of the tissue damage, which may occur in some cases of IM. Of note, some experimental studies suggest that dilated cardiomyopathy could be a consequence of untreated IM. However, further research is required to address the molecular mechanisms that may link these two clinical entities. Here we review the mechanisms involved in the regulation at different levels of the immune response during IM, with a special focus on diagnostic and therapeutic perspectives of molecules that have been linked to the development of IM and the resulting chronic heart diseases.


Assuntos
Cardiomiopatia Dilatada/etiologia , Insuficiência Cardíaca/etiologia , Miocardite/imunologia , Animais , Cardiomiopatia Dilatada/imunologia , Cardiomiopatia Dilatada/fisiopatologia , Doença Crônica , Insuficiência Cardíaca/imunologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/fisiopatologia , Miocardite/complicações , Miocardite/diagnóstico , Fatores de Tempo
7.
Eur J Immunol ; 44(2): 469-79, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24165808

RESUMO

Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD-1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD-1-deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type-1 cytokine responses (IL-12 and IFN-γ). PD-1⁻/⁻ DCs showed no cell intrinsic defect in IL-12 production in vitro. Instead, PD-1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL-10 release, which impaired type-1-inflammation during infection. Our results indicate that the absence of PD-1 increases IL-10 production even in the absence of infection. Although the possibility that such increased IL-10 protects against autoimmune damage is speculative, our results show that IL-10 suppresses the development of protective Th1 immune response after T. gondii infection.


Assuntos
Interleucina-10/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Toxoplasmose Animal/metabolismo , Animais , Inflamação/imunologia , Inflamação/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Toxoplasma/imunologia , Toxoplasma/metabolismo , Toxoplasmose Animal/imunologia
8.
Microbes Infect ; 16(1): 28-39, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24140555

RESUMO

The infection with Trypanosoma cruzi induces a robust cardiac inflammation that plays a pathogenic role in the development of Chagas heart disease. In this study, we aimed at investigating the effects of Haem Oxygenase (HO) during experimental infection by T. cruzi in BALB/c and C57BL/6 mice. HO has recently emerged as a key factor modulating the immune response in diverse models of inflammatory diseases. In mice with two different genetic backgrounds, the pharmacologic inhibition of HO activity with zinc-protoporphyrin IX (ZnPPIX) induced enhanced myocarditis and reduced parasitaemia, which was accompanied by an amplified production of nitric oxide and increased influx of CD4(+), CD8(+) and IFN-γ(+) cells to the myocardium in comparison with the control group. Conversely, treatment with haemin (an activator of HO) lead to a decreased number of intracardiac CD4(+) (but not CD8(+)) cells compared to the control group. The mechanism involved in these observations is a modulation of the induction of regulatory T cells, because the stimulation or inhibition of HO was parallelled by an enhanced or reduced frequency of regulatory T cells, respectively. Hence, HO may be involved in the regulation of heart tissue inflammation and could be a potential target in conceiving future therapeutic approaches for Chagas disease.


Assuntos
Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/metabolismo , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Animais , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Hemina/administração & dosagem , Hemina/farmacologia , Inflamação/patologia , Camundongos , Óxido Nítrico/biossíntese , Protoporfirinas/administração & dosagem , Protoporfirinas/farmacologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Trypanosoma cruzi
9.
Mediators Inflamm ; 2013: 167086, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24222935

RESUMO

Statins are pharmacological inhibitors of the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), an enzyme responsible for the synthesis of cholesterol. Some recent experimental studies have shown that besides their effects on the primary and secondary prevention of cardiovascular diseases, statins may also have beneficial anti-inflammatory effects through diverse mechanisms. On the other hand, the induction and activity of regulatory T cells (Treg) are key processes in the prevention of pathology during chronic inflammatory and autoimmune diseases. Hence, strategies oriented towards the therapeutic expansion of Tregs are gaining special attention among biomedical researchers. The potential effects of statins on the biology of Treg are of particular importance because of their eventual application as in vivo inducers of Treg in the treatment of multiple conditions. In this paper we review the experimental evidence pointing out to a potential effect of statins on the role of regulatory T cells in different conditions and discuss its potential clinical significance.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Células Apresentadoras de Antígenos/citologia , Doenças Autoimunes/metabolismo , Movimento Celular/efeitos dos fármacos , Colesterol/sangue , Células Dendríticas/citologia , Regulação da Expressão Gênica , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inflamação/metabolismo , Camundongos , Fenótipo , Células Th1/efeitos dos fármacos
10.
PLoS One ; 8(10): e78367, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24205212

RESUMO

BACKGROUND: Chagas disease affects approximately 10 million people mainly in Latin America. The immune regulation by the host seems to be an essential factor for disease evolution, and immune system inhibitory molecules such as CTLA-4 and PD-1 favor the maintenance of peripheral tolerance. Considering that polymorphisms at the immunoregulatory CTLA-4 and PDCD1 genes may alter their inhibitory function, we investigated the association of alleles, genotypes and haplotypes of polymorphic sites observed at the CTLA-4 and PDCD1 genes with different clinical manifestations of chronic Chagas disease (indeterminate, cardiac, digestive and mixed). METHODS: The polymorphisms at the CTLA-4 (-1722T/C, -318C/T and +49A/G) and PDCD1 (PD-1.3G/A) genes were typed using TaqMan methodology in 277 chronic Chagas disease patients classified into four groups, according to clinical characteristics, and 326 non-infected controls. RESULTS: Our results showed that CTLA-4 -1722CC genotype (22%), -1722C allele (27%) and CTLA-4 TCG (8.6%), TCA (26%) and CCA (15%) haplotypes were strongly associated with the indeterminate form, while the CTLA-4-318CT genotype (82%) and CTLA-4-318T allele (47%) were found mainly in patients with the mixed form of the disease. The CTLA-4 TCG haplotype (10.2%) was associated with the digestive form. On the other hand, the PD-1.3G/A polymorphism was not associated with chronic Chagas disease and its clinical manifestations. CONCLUSIONS: Here, we showed that alleles, genotypes and haplotypes reported to increase the expression of the regulatory molecule CTLA-4 were associated with the indeterminate form of the disease. Taken together, our data support the idea that polymorphic sites at immunoregulatory genes may influence the development of Chagas disease variants.


Assuntos
Doença de Chagas/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Estudos de Casos e Controles , Doença Crônica , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética
11.
J Immunol ; 191(6): 3373-83, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23966627

RESUMO

The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain-like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1ß and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain-containing 3 (NLRP3), but not NLR family, caspase recruitment domain-containing 4 or NLR family, pyrin domain-containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1ß. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K⁺ efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-γ production in the heart, ASC⁻/⁻ and caspase-1⁻/⁻ infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.


Assuntos
Doença de Chagas/imunologia , Proteínas do Citoesqueleto/imunologia , Resistência à Doença/imunologia , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Animais , Proteínas Reguladoras de Apoptose , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/imunologia , Caspase 1/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Análise de Sequência com Séries de Oligonucleotídeos , Trypanosoma cruzi/imunologia
12.
Nat Med ; 19(7): 909-15, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23749230

RESUMO

Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome-deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1ß (IL-1ß) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production.


Assuntos
Resistência à Doença/efeitos dos fármacos , Inflamassomos/imunologia , Interleucina-1beta/metabolismo , Leishmania , Óxido Nítrico/imunologia , Animais , Proteínas Reguladoras de Apoptose , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/genética , Células Cultivadas , Proteínas do Citoesqueleto/genética , Resistência à Doença/genética , Resistência à Doença/imunologia , Feminino , Leishmaniose/genética , Leishmaniose/imunologia , Leishmaniose/metabolismo , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Óxido Nítrico Sintase Tipo II/genética
13.
PLoS Negl Trop Dis ; 7(3): e2113, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505592

RESUMO

The purpose of this study was to calculate the seroprevalence of Trypanosoma cruzi infection in a sample of inhabitants from a region considered to be at high risk of natural transmission of Chagas disease in Colombia. A cross-sectional study was conducted in subjects from 5 municipalities, recruited in urban and rural locations, distributed by gender according to the demographic information available. Socio-demographic information, history of potential exposure to insect vectors, blood donating, as well as symptoms suggesting cardiac disease were collected using a questionnaire. After giving written informed consent, blood specimens were obtained from 486 people to determine the serologic evidence of past exposure to T. cruzi. Infection was diagnosed when two different tests (ELISA and IHA) were positive. The seroprevalence of antibodies against T. cruzi was 16.91% considering an estimated population of 44,355 aged between 15 and 89 years (95%IC: 13.72 to 20.01). The factors significantly associated with the infection were: 1- Housing materials like vegetable material, adobe or unfinished brick walls; 2- The fact of having previous tests for Chagas disease (regardless of the result). Of note, the mean ages among infected and not infected participants were significantly different (49.19 vs. 41.66, p ≤ 0.0001). Among the studied municipalities, the one with the highest frequency of T. cruzi infection was Nunchia, with 31.15% of the surveyed subjects. Therefore it may be concluded that T. cruzi infection is highly prevalent in the north region of Casanare, in Colombia.


Assuntos
Anticorpos Anti-Helmínticos/sangue , Doença de Chagas/epidemiologia , Trypanosoma cruzi/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colômbia/epidemiologia , Estudos Transversais , Demografia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estudos Soroepidemiológicos , Inquéritos e Questionários , Adulto Jovem
14.
PLoS One ; 8(2): e56347, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23409175

RESUMO

The development of Chagas disease is determined by a complex interaction between the genetic traits of both the protozoan parasite, T. cruzi, and the infected host. This process is regulated by multiple genes that control different aspects of the host-parasite interaction. While determination of the relevant genes in humans is extremely difficult, it is feasible to use inbred mouse strains to determine the genes and loci responsible for host resistance to infection. In this study, we investigated the susceptibility of several inbred mouse strains to infection with the highly virulent Y strain of T. cruzi and found a considerable difference in susceptibility between A/J and C57BL/6 mice. We explored the differences between these two mouse strains and found that the A/J strain presented higher mortality, exacerbated and uncontrolled parasitemia and distinct histopathology in the target organs, which were associated with a higher parasite burden and more extensive tissue lesions. We then employed a genetic approach to assess the pattern of inheritance of the resistance phenotype in an F1 population and detected a strong parent-of-origin effect determining the susceptibility of the F1 male mice. This effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing. Collectively, our genetic approach of using the F1 population suggests that genes contained in the murine chromosome X contribute to the natural resistance against T. cruzi infection. Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.


Assuntos
Doença de Chagas/genética , Hibridização Genética , Trypanosoma cruzi/fisiologia , Animais , Suscetibilidade a Doenças , Feminino , Loci Gênicos/genética , Masculino , Camundongos , Fenótipo , Caracteres Sexuais , Especificidade da Espécie , Cromossomo X/genética
15.
Expert Rev Anti Infect Ther ; 10(11): 1279-82, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23241184

RESUMO

Evaluation of: Bua J, Volta BJ, Velazquez EB et al. Vertical transmission of Trypanosoma cruzi infection: quantification of parasite burden in mothers and their children by parasite DNA amplification. Trans. R. Soc. Trop. Med. Hyg. 106(10), 623-628 (2012). The congenital transmission of Trypanosoma cruzi has gained epidemiological importance because it is partially responsible for the spread of Chagas disease worldwide. The feasibility of a cure when infected children are treated early makes the detection of congenital infection a valuable goal toward the control of the disease. Here, the authors review and discuss the findings of Bua et al., who quantified the parasitemia of infected women and their newborns by quantitative PCR. The authors demonstrate that the maternal parasite burden is directly related to the risk of neonatal infection. This study points out the importance of a quantitative screen for T. cruzi in pregnant women who live in, or have traveled to, endemic areas for improving the diagnosis of infected newborns and providing prompt treatment.

16.
Trop Med Int Health ; 17(9): 1057-65, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22686518

RESUMO

Chronic chagasic cardiomyopathy affects 20% of Chagas' disease patients. At present, Chagas' disease chemotherapy uses nitrofurans, benznidazole (Rochagan®, Rodanil®, Roche) or nifurtimox (Lampit®, Bayer). Treatment during acute and recent chronic phases in childhood effects 71.5% and 57.6%, respectively, of parasitological cure. However, in clinical trials during the late chronic phase, only 5.9% of parasitological cure were achieved. This review focuses on the benefit from aetiological treatment to avoid, stop or revert myocarditis. Divergent data gathered from clinical practice are not convincing to support prescription of aetiological treatment as routine for indeterminate and cardiac chronic patients.


Assuntos
Antiparasitários/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Trypanosoma cruzi , Doença Aguda , Antiparasitários/administração & dosagem , Antiparasitários/efeitos adversos , Doença Crônica , Ensaios Clínicos como Assunto , Humanos
17.
PLoS Negl Trop Dis ; 6(4): e1630, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22545173

RESUMO

BACKGROUND: Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: First, we observed CD4(+)IL-17(+) T cells in culture of peripheral blood mononuclear cells (PBMC) from Chagas' disease patients and we evaluated Th1, Th2, Th17 cytokine profile production in the PBMC cells from Chagas' disease patients (cardiomyopathy-free, and with mild, moderate or severe cardiomyopathy) cultured with T. cruzi antigen. Cultures of PBMC from patients with moderate and severe cardiomyopathy produced high levels of TNF-α, IFN-γ and low levels of IL-10, when compared to mild cardiomyopathy or cardiomyopathy-free patients. Flow cytometry analysis showed higher CD4(+)IL-17(+) cells in PBMC cultured from patients without or with mild cardiomyopathy, in comparison to patients with moderate or severe cardiomyopathy. We then analyzed the presence and function of regulatory T cells in all patients. All groups of Chagas' disease patients presented the same frequency of CD4(+)CD25(+) regulatory T cells. However, CD4(+)CD25(+) T cells from patients with mild cardiomyopathy or cardiomyopathy-free showed higher suppressive activity than those with moderate and severe cardiomyopathy. IFN-γ levels during chronic Chagas' disease are inversely correlated to the LVEF (P = 0.007, r = -0.614), while regulatory T cell activity is directly correlated with LVEF (P = 0.022, r = 0.500). CONCLUSION/SIGNIFICANCE: These results indicate that reduced production of the cytokines IL-10 and IL-17 in association with high levels of IFN-γ and TNF-α is correlated with the severity of the Chagas' disease cardiomyopathy, and the immunological imbalance observed may be causally related with deficient suppressor activity of regulatory T cells that controls myocardial inflammation.


Assuntos
Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/patologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD4/análise , Células Cultivadas , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/análise , Leucócitos Mononucleares/química , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade
18.
Neuroimmunomodulation ; 18(5): 328-38, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21952685

RESUMO

During immune response to infectious agents, the host develops an inflammatory response which could fail to eliminate the pathogen or may become dysregulated. In this case, the ongoing response acquires a new status and turns out to be detrimental. The same elements taking part in the establishment and regulation of the inflammatory response (cytokines, chemokines, regulatory T cells and counteracting compounds like glucocorticoids) may also mediate harmful effects. Thymic disturbances seen during Trypanosoma cruzi (T. cruzi) infection fit well with this conceptual framework. After infection, this organ suffers a severe atrophy due to apoptosis-induced thymocyte exhaustion, mainly affecting the immature double-positive (DP) CD4+CD8+ population. Thymus cellularity depletion, which occurs in the absence of main immunological mediators involved in anti-T. cruzi defense, seems to be linked to a systemic cytokine/hormonal imbalance, involving a dysregulated increase in Tumor Necrosis Factor alpha (TNF-α) and corticosterone hormone levels. Additionally, we have found an anomalous exit of potentially autoimmune DP cells to the periphery, in parallel to a shrinkage in the compartment of natural regulatory T cells. In this context, our data clearly point to the view that the thymus is a target organ of T. cruzi infection. Preserved thymus may be essential for the development of an effective immune response against T. cruzi, but this organ is severely affected by a dysregulated circuit of proinflammatory cytokines and glucocorticoids. Also, the alterations observed in the DP population might have potential implications for the autoimmune component of human Chagas disease.


Assuntos
Alergia e Imunologia , Doença de Chagas , Endocrinologia , Timo/imunologia , Timo/metabolismo , Antígenos CD/metabolismo , Doença de Chagas/imunologia , Doença de Chagas/metabolismo , Doença de Chagas/patologia , Citocinas/metabolismo , Glucocorticoides/metabolismo , Humanos , Timo/patologia
19.
Expert Rev Anti Infect Ther ; 9(5): 609-20, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21609270

RESUMO

Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.


Assuntos
Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Miocardite/etiologia , Tripanossomicidas/efeitos adversos , Trypanosoma cruzi/fisiologia , Adulto , Animais , Doença de Chagas/complicações , Doença de Chagas/mortalidade , Criança , Ensaios Clínicos como Assunto , Esquema de Medicação , Humanos , América Latina/epidemiologia , Camundongos , Miocardite/mortalidade , Miocardite/parasitologia , Miocardite/fisiopatologia , Nifurtimox/efeitos adversos , Nifurtimox/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Análise de Sobrevida , Tripanossomicidas/uso terapêutico
20.
Infect Immun ; 79(5): 1873-81, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21357717

RESUMO

Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.


Assuntos
Antígenos de Superfície/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Cardiomiopatia Chagásica/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Trypanosoma cruzi/imunologia , Animais , Antígenos de Superfície/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Separação Celular , Cardiomiopatia Chagásica/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor de Morte Celular Programada 1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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