RESUMO
Human chronic Chagas disease cardiomyopathy (CCC) is an inflammatory-dilated cardiomyopathy occurring years after infection by the protozoan Trypanosoma cruzi. The heart inflammatory infiltrate in CCC shows a 2:1 predominance of CD8(+) in relation to CD4(+) T cells, with a typical Th1-type cytokine profile. However, in vitro expansion of infiltrating T cells from heart biopsy-derived fragments with interleukin-2 (IL-2) and phytohaemagglutinin leads to the outgrowth of CD4(+) over CD8(+) T cells. We hypothesized that survival cytokines, such as IL-2, IL-7 and IL-15 might be differentially involved in the growth and maintenance of heart-infiltrating and peripheral CD8(+) T cells from CCC patients. We found that IL-7 and IL-15 were superior to IL-2 in the expansion and viability of CD8(+) T cells from both PBMC and heart-infiltrating T-cell lines from CCC patients, and the combination of the three cytokines showed synergic effects. Heart-infiltrating CD8(+) T cells showed higher expression of both IL-15R alpha and gamma(c) chain than CD4(+) T cells, which may explain the improvement of CD8(+) T-cell growth in the presence of IL-2 + IL-7 + IL-15. Immunohistochemical identification of IL-15 and the higher mRNA expression of IL-15R alpha, IL-7 and gamma(c) chain in CCC heart tissues compared with control individuals indicate in situ production of survival cytokines and their receptors in CCC hearts. Together, our results suggest that local production of IL-7 and IL-15 may be associated with the maintenance and predominance of CD8(+) T cells, the cells effecting tissue damage in CCC hearts.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Cardiomiopatia Chagásica/imunologia , Cardiomiopatia Chagásica/patologia , Interleucina-15/biossíntese , Interleucina-7/biossíntese , Miocárdio/imunologia , Miocárdio/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Movimento Celular/imunologia , Proliferação de Células , Sobrevivência Celular/imunologia , Cardiomiopatia Chagásica/metabolismo , Doença Crônica , Humanos , Imunofenotipagem , Interleucina-15/fisiologia , Interleucina-2/biossíntese , Interleucina-2/fisiologia , Interleucina-7/fisiologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Contagem de Linfócitos , Miocárdio/metabolismoRESUMO
Alloreactive T cells recognize donor antigens by two routes: direct and indirect pathways of allorecognition. Although the direct pathway is reported to be dominant in allograft rejection, indirect allorecognition also plays an important role. Indirect alloreactivity is also observed in renal transplant patients irrespective of rejection. Previously we showed a predominance of interleukin (IL)-10 induced by indirect allorecognition of donor human leucocyte antigen (HLA)-DR peptides, suggesting the existence of indirect alloreactive T cells displaying regulatory activity. In the present work, our objective was to characterize these regulatory T cells. We detected indirect alloproliferation of peripheral blood mononuclear cells (PBMC) from renal transplant patients, induced by donor HLA-DR peptides, dependent on IL-4 or IL-10, suggesting regulatory activity as part of the alloreactive T-cell repertoire. PBMC-derived indirect alloreactive T-cell lines were established and produced both inflammatory and regulatory cytokines. We showed that two of these T-cell lines which were able to inhibit both direct and indirect alloproliferation of another T-cell line from the same patient presented a CD4(+)CD25(+)Foxp3(+) T-cell population. These data support the idea that indirect alloreactive T cells may also have regulatory activity and may contribute to the maintenance of the human renal allograft.
Assuntos
Apresentação de Antígeno/imunologia , Fatores de Transcrição Forkhead/biossíntese , Transplante de Rim/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adolescente , Adulto , Idoso , Proliferação de Células , Criança , Humanos , Pessoa de Meia-Idade , Tolerância a Antígenos Próprios/imunologiaRESUMO
Os efeitos histopatológicos do cádmio nas brânquias de tilápia Oreochromis niloticus foram estudados por microscopia óptica, usando 25mgl-1 de CdCl2 durante quatro dias, com o objetivo de identificar seus efeitos agudos na estrutura das brânquias. A morfologia geral das brânquias de O. niloticus é idêntica à de outros teleósteos, apresentando quatro pares de arcos branquiais com filamentos bem desenvolvidos. Situadas lateralmente, encontram-se as lamelas provenientes do eixo central dos filamentos. No epitélio filamentar foi possível identificar células de cloro, pavimentosas e mucosas. Os peixes expostos ao cádmio mostraram sinais de lesões epiteliais; edema intersticial, vasodilatação das lamelas, destacamento do epitélio lamelar e proliferação do epitélio filamentar. As alterações observadas também incluíram fusão nas lamelas como resultado de hiperplasia e hipertrofia epitelial, ruptura do sistema de células pilar, aneurismas e necroses.
The histopathogical effects of cadmium on the gills of tilapia Oreochromis niloticus were studied by light microscopy, using 25mgl-1 of CdCl2 during four days to identified the effects of short-term exposure on gills structure. The general morphology of O. niloticus gills is similar to the other teleostean fishes, showing four pairs of gills arches with well developed filaments. Bilaterally situated, secondary lamellae branches are found from the central axis of the filaments. The filamentar epithelium showed the chloride cells, the pavement cells and mucous cells. Fish exposed to cadmium showed signs of epithelial lesion, namely the interstitial edema, swollen of the lamellae, lifting and cellular proliferation of the filamentar epithelium. The changes of the gills also included lamellar fusion as a result of epithelial hyperplasia and hypertrophy, the breakdown of pillar cell system, and aneurisms with some ruptures and necrosis, especially in the filamentar epithelium.
Assuntos
Brânquias/anatomia & histologia , Ciclídeos , Intoxicação por Cádmio/complicações , Intoxicação por Cádmio/diagnóstico , Microscopia/métodosRESUMO
Os efeitos histopatológicos do cádmio nas brânquias de tilápia Oreochromis niloticus foram estudados por microscopia óptica, usando 25mgl-1 de CdCl2 durante quatro dias, com o objetivo de identificar seus efeitos agudos na estrutura das brânquias. A morfologia geral das brânquias de O. niloticus é idêntica à de outros teleósteos, apresentando quatro pares de arcos branquiais com filamentos bem desenvolvidos. Situadas lateralmente, encontram-se as lamelas provenientes do eixo central dos filamentos. No epitélio filamentar foi possível identificar células de cloro, pavimentosas e mucosas. Os peixes expostos ao cádmio mostraram sinais de lesões epiteliais; edema intersticial, vasodilatação das lamelas, destacamento do epitélio lamelar e proliferação do epitélio filamentar. As alterações observadas também incluíram fusão nas lamelas como resultado de hiperplasia e hipertrofia epitelial, ruptura do sistema de células pilar, aneurismas e necroses.(AU)
The histopathogical effects of cadmium on the gills of tilapia Oreochromis niloticus were studied by light microscopy, using 25mgl-1 of CdCl2 during four days to identified the effects of short-term exposure on gills structure. The general morphology of O. niloticus gills is similar to the other teleostean fishes, showing four pairs of gills arches with well developed filaments. Bilaterally situated, secondary lamellae branches are found from the central axis of the filaments. The filamentar epithelium showed the chloride cells, the pavement cells and mucous cells. Fish exposed to cadmium showed signs of epithelial lesion, namely the interstitial edema, swollen of the lamellae, lifting and cellular proliferation of the filamentar epithelium. The changes of the gills also included lamellar fusion as a result of epithelial hyperplasia and hypertrophy, the breakdown of pillar cell system, and aneurisms with some ruptures and necrosis, especially in the filamentar epithelium.(AU)
Assuntos
Ciclídeos/anatomia & histologia , Brânquias/anatomia & histologia , Microscopia/métodos , Intoxicação por Cádmio/complicações , Intoxicação por Cádmio/diagnósticoRESUMO
Alloreactive T cells recognize donor antigens by two routes: direct and indirect pathways of allorecognition. Although the direct pathway is reported to be dominant in allograft rejection, indirect allorecognition also plays an important role. Indirect alloreactivity is also observed in renal transplant patients irrespective of rejection. Previously we showed a predominance of interleukin (IL)-10 induced by indirect allorecognition of donor human leucocyte antigen (HLA)-DR peptides, suggesting the existence of indirect alloreactive T cells displaying regulatory activity. In the present work, our objective was to characterize these regulatory T cells. We detected indirect alloproliferation of peripheral blood mononuclear cells (PBMC) from renal transplant patients, induced by donor HLA-DR peptides, dependent on IL-4 or IL-10, suggesting regulatory activity as part of the alloreactive T-cell repertoire. PBMC-derived indirect alloreactive T-cell lines were established and produced both inflammatory and regulatory cytokines. We showed that two of these T-cell lines which were able to inhibit both direct and indirect alloproliferation of another T-cell line from the same patient presented a CD4+CD25 +Foxp3+ T-cell population. These data support the idea that indirect alloreactive T cells may also have regulatory activity and may contribute to the maintenance of the human renal allograft.
Assuntos
Masculino , Feminino , Humanos , Criança , Adolescente , Adulto , /citologia , /imunologiaRESUMO
Autoreactivity to heat shock protein 60 (Hsp60) has been implicated in the pathogenesis and regulation of chronic inflammation, especially in autoimmune diseases. In transplantation, there is a lack of information regarding the cytokine profile and specificity of cells that recognize self-Hsp60 as well as the kinetics of autoreactivity following transplantation. We studied the cellular reactivity of peripheral and graft-infiltrating lymphocytes against Hsp60 in renal transplant patients. Cytokine production induced by this protein in peripheral blood mononuclear cells indicated a predominance of interleukin (IL)-10 during the late post-transplantation period, mainly in response to intermediate and C-terminal peptides. Patients with chronic rejection presented reactivity to Hsp60 with a higher IL-10/interferon (IFN)-gamma ratio compared to long-term clinically stable patients. Graft-infiltrating T cell lines, cocultured with antigen-presenting cells, preferentially produced IL-10 after Hsp60 stimulation. These results suggest that, besides its proinflammatory activity, autoreactivity to Hsp60 in transplantation may also have a regulatory role.
Assuntos
Chaperonina 60/imunologia , Transplante de Rim/imunologia , Adolescente , Adulto , Autoimunidade , Linhagem Celular , Criança , Doença Crônica , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática/métodos , Rejeição de Enxerto/imunologia , Humanos , Imunofenotipagem , Interferon gama/biossíntese , Interleucina-10/biossíntese , Rim/imunologia , Pessoa de Meia-Idade , Período Pós-Operatório , Subpopulações de Linfócitos T/imunologiaRESUMO
We showed previously that exposure to microcystin-LR causes renal toxic effects in isolated perfused rat kidney, and that inflammatory mediators from supernatants of macrophages stimulated by microcystin-LR are involved in this process. The aim of this research was to examine water and electrolytes secretion in vivo, induced by microcystin-LR and supernatant of macrophages stimulated for this toxin (SUP.MphiS + MCLR), using perfused rat ileal segment and ligated intestinal loop models. We found microcystin-LR at 1 microg/ml (0.09 +/- 0.003* vs. control 0.07 +/- 0.001 g of secretion/2 cm of loop; P < 0.05*) and the SUP.MphiS + MCLR after 18 h postinoculation (0.10 +/- 0.003 vs. control 0.03 +/- 0.002 g/cm) caused intestinal secretion. In addition, microcystin-LR caused significant sodium secretion (-2.18 +/- 0.72* vs. control 2.18 +/- 0.50 microEq g(-1) min(-1)), potassium (-0.26 +/- 0.04* vs. control 0.32 +/- 0.03 microEq g(-1) min(-1)), chloride (MCLR = -3.29 +/- 1.93* vs. control 0.88 +/- 1.25 microEq g(-1) min(-1)) and water (-0.012 +/- 0.004* vs. control 0.002 +/- 0.002 ml g(-1) min(-1)). We also demonstrated SUP.MphiS + MCLR to induce intestinal secretion of electrolytes (sodium, potassium, chloride) and water. These findings suggested that microcystin-LR and lamina propria macrophages-derived mediators are able to induce intestinal secretion in vivo, probably via inhibition of protein phosphatase.
Assuntos
Eletrólitos/metabolismo , Secreções Intestinais/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Água/metabolismo , Animais , Inibidores Enzimáticos/farmacologia , Íleo/efeitos dos fármacos , Íleo/metabolismo , Secreções Intestinais/metabolismo , Macrófagos/efeitos dos fármacos , Toxinas Marinhas , Microcistinas , Fosfoproteínas Fosfatases/antagonistas & inibidores , Ratos , Ratos Sprague-DawleyRESUMO
Chemotherapy-induced mucositis is an important dose-limiting and costly side effect for which there is no definitive prophylaxis or treatment. This is due in part to the lack of understanding of its pathophysiology and impact on intestinal function. The objectives of this study were to investigate the small intestine barrier function and electrolyte and water transport in an experimental model of methotrexate-induced mucositis, and to correlate these alterations with histological damage. Wistar rats were treated with methotrexate (1.5-3.5 mg/kg) for 3 days to induce mucositis. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following administration by gavage. Intestinal perfusion was performed in vivo for evaluation of water and electrolyte transports. Methotrexate-treated rats lost a significant amount of weight and presented a marked reduction in food intake. Methotrexate induced significant and dose-dependent villous atrophy and elongation of crypts in duodenum, jejunum, and ileum. Methotrexate also induced an increase in sodium and potassium secretion and an important reduction of the mucosa absorptive surface area, shown by the decrease in the mannitol excretion ratio. In conclusion, methotrexate caused major changes in small bowel function by disrupting intestinal permeability and inducing electrolyte secretion in parallel with substantial histological damage.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Metotrexato/farmacologia , Estomatite/fisiopatologia , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Transporte Biológico/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Duodeno , Ingestão de Alimentos , Íleo , Mucosa Intestinal , Jejuno , Masculino , Metotrexato/administração & dosagem , Potássio/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Estomatite/induzido quimicamente , Água/metabolismo , Redução de PesoAssuntos
Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Cardiomiopatia Chagásica , Eletrofisiologia , Sistema de Condução CardíacoRESUMO
Os autores analisam a eletrofisiologia do nodulo sinusal de 31 portadores de cardiopatia chagasica cronica, com conducao AV 1:1 e varias formas de bloqueio de ramo ao ECG. Utilizam, como metodologia, a medida do tempo de recuperacao do nodulo simusal corrigido, determinado por estimulacao atrial continua e parada brusca da unidade geradora; a medida do tempo de conducao sino-atrial obtido por extra-estimulos pelas relacoes A1A2/A2A3 em seus percentuais sobre A1A1. Os resultados demonstram uma alta incidencia de transtornos do tecido perissinusal, sugerindo a existencia, nos casos de disfuncao sinusal em chagasicos, de um mecanismo misto de producao, envolvendo o automatismo celular e a condutividade tecidual. Sugerem que as lesoes do tecido perissinusal favorecem o aparecimento de mecanismos de reentrada, bem como representam fator de limitacao para a medida do tempo de recuperacao do nodulo sinusal. Descrevem, com os extra-extimulos um possivel novo tipo de fenomeno de "gap" ocorrendo entre o tecido atrial e a juncao sino-atrial