Assuntos
Adjuvantes Imunológicos/efeitos adversos , Hepatite/etiologia , Interferon beta/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Adulto , Feminino , Humanos , Interferon beta-1a , Interferon beta/uso terapêutico , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológicoRESUMO
Gastric variceal hemorrhage is associated with a high morbidity and mortality. We report the efficacy and safety of bovine thrombin in the treatment of bleeding gastric varices. At endoscopy 52 patients with hematemesis were diagnosed with bleeding gastric varices. Patients were treated by intravariceal injection with bovine thrombin and underwent further endoscopy at 72 hr and then at two-week intervals. Initial hemostasis was achieved in 49/52 patients (94%). Bleeding-related mortality at 72 hr after the index bleed was 3/52 (6%). The mean amount of thrombin used to achieve initial hemostasis was 1070 IU (range 400-2000 IU) and no adverse drug effects were observed. The median number of treatment sessions required to achieve gastric variceal ablation was 2 (range 1-3). At six weeks, 9 of 49 surviving patients (18%) rebled and one further patient died. The six-week mortality in patients treated with thrombin was 4/52 (8%). In conclusion, safe and effective hemostasis of bleeding gastric varices can be achieved by intravariceal injection with thrombin.
Assuntos
Varizes Esofágicas e Gástricas/tratamento farmacológico , Hemorragia Gastrointestinal/tratamento farmacológico , Hemostáticos/uso terapêutico , Trombina/uso terapêutico , Adulto , Idoso , Endoscopia Gastrointestinal , Feminino , Humanos , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Concentrations of pro-inflammatory cytokines are raised in the small intestine of patients with coeliac disease after ingestion of gluten but there are equivalent data on interleukin-4 (IL-4) and interleukin-10 (IL-10) producing cells. These cytokines are known to exert important regulatory effects on pro-inflammatory cytokine production from lymphocytes and macrophages. AIMS: To investigate whether there is a primary deficiency of IL-4 and IL-10 producing cells and their site of production in the small intestine of patients with coeliac disease in relation to the changes in inflammatory cell infiltrate. PATIENTS: Jejunal biopsy specimens from patients with coeliac disease (11 untreated, 10 treated) and nine disease controls were studied. METHODS: Immunohistochemical staining of sections for IL-4 and IL-10 cytokines and the cell phenotypic markers CD3 (T lymphocytes) and CD45 (total inflammatory cell infiltrate) was carried out using monoclonal antibodies. Expression of IL-4 and IL-10 messenger RNA was detected by in situ hybridisation with oligonucleotide probe cocktails for each cytokine. RESULTS: IL-4 and IL-10 mRNA and protein were detected in the lamina propria of treated and untreated coeliac patients and disease controls but not in the epithelium. A significant increase in the number of CD45 (p < 0.005) and CD3 (p < 0.05) positive cells was found in the lamina propria of patients with untreated coeliac disease compared with treated coeliac patients and disease controls but there were no differences in IL-4 or IL-10 between these groups with either method. CONCLUSIONS: There is no primary deficiency of IL-4 and IL-10 producing cells in the small intestine of patients with coeliac disease. Detectable concentrations of IL-4 and IL-10 were found in control patients which suggests that these cytokines are involved in normal mucosal immunoregulation. The increased number of T lymphocytes but not IL-4 or IL-10 producing cells in the lamina propria of patients with untreated than in those with treated disease suggests not only that the lamina propria is the major mucosal compartment for cytokine production but that newly recruited mucosal T lymphocytes are directed to a predominant Th1 and not a Th2 cytokine response in coeliac patients on a diet containing gluten.
Assuntos
Doença Celíaca/imunologia , Interleucinas/análise , Intestino Delgado/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Celíaca/dietoterapia , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Interleucina-10/análise , Interleucina-10/genética , Interleucina-4/análise , Interleucina-4/genética , Interleucinas/genética , Mucosa Intestinal/imunologia , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análiseRESUMO
Cytokines mediate immune responses and are detectable in the normal gastrointestinal mucosa. It is unclear how cytokines are physiologically regulated but in inflammatory enteropathies their expression is often greatly increased and may account for the tissue damage observed. T-cells may be sub-divided according to the pattern of cytokines which they secrete. TH1 cytokine expression is increased in delayed type IV cell mediate immune responses whereas TH2 cytokines are raised in diseases in which humoral mechanisms are more important. Cytokines are secreted by macrophages in relatively greater amounts than from T-cells. They are non-specific products of inflammation and may account for the majority of tissue damage seen in mucosal disease. The pattern of cytokine secretion may determine the immunopathogenesis of an inflammatory disorder. The ultimate goal of cytokine research is the development of therapeutic measures based on a better understanding of their actions which may be achieved with a better understanding of the molecular immune-microenvironment in inflammatory enteropathies. Studies with transgenic mice and gene targeted mice have important implications to the understanding of the immune system and its role in intestinal diseases.
Assuntos
Citocinas/análise , Gastroenteropatias/metabolismo , Animais , HumanosRESUMO
This study investigated the presence of mRNA coding for interferon gamma (IFN gamma), tumour necrosis factor alpha (TNF alpha), and interleukins 2 (IL2) and 6 (IL6), in the mucosa of four coeliac patients in remission who had been challenged with either gliadin or synthetic gliadin oligopeptides. Jejunal biopsy specimens from these patients, taken before and at two, four, and six hours after challenge, were hybridised with specific 35S-labelled DNA oligonucleotide probes. The lamina propria of all the patients contained significantly increased numbers of cytokine mRNA expressing cells four hours after challenge with gliadin or an oligopeptide corresponding to amino acids 31-49 of A-gliadin (peptide A). No significant changes were seen with the peptides corresponding to aminoacids 202-220 (peptide B) or 3-21 (peptide C) of A-gliadin, with the exception of one patient who showed a significant increase in the number of TNF alpha mRNA expressing cells four hours after challenge with peptide B. In vivo studies in coeliac disease have shown that significant histological changes occur in the mucosa of treated coeliac patients four hours after challenge with either gliadin or peptide A. These findings suggest that the histological changes seen previously in the mucosa of coeliac patients after wheat peptide challenge may be caused by increased expression of cytokines within the mucosa.
Assuntos
Doença Celíaca , Interferon gama/análise , Interleucina-2/análise , Interleucina-6/análise , RNA Mensageiro/análise , Fator de Necrose Tumoral alfa/análise , Adulto , Idoso , Sequência de Bases , Northern Blotting , Sondas de DNA , Gliadina , Humanos , Mucosa Intestinal/química , Pessoa de Meia-Idade , Dados de Sequência Molecular , Peptídeos , Sensibilidade e EspecificidadeRESUMO
The isolation of gliadin specific HLA-DQ2 restricted T lymphocyte clones from the intestinal mucosa of patients with coeliac disease supports a role for cell mediated immunity in the pathogenesis of this condition. Whether supernatants from immune activated T cell clones could produce histological damage to duodenal mucosa in vitro was studied. Biopsy specimens were obtained from 18 patients without coeliac disease or any other demonstrable abnormality. The tissue was maintained in organ culture for 24 hours with organ culture medium alone, with supernatant from gliadin sensitive T cell clones that had (B) or had not (A) been stimulated with gluten, and compared with the effects caused by the addition of interferon gamma to the organ culture medium. Both the (B) supernatants (1:100) and interferon gamma (100 IU/ml) produced a significant reduction in the enterocyte height (21:5 (3.4) microns and 21.0 (3.2) microns respectively, each p < 0.001) compared with specimens grown in organ culture medium alone (27.3 (2.8) microns). The toxic effects of (B) supernatants could be blocked by pre-incubating them with anti-interferon gamma antibody. These findings support the role of gliadin sensitive T lymphocytes in the immune pathogenesis of coeliac disease and their secretion of interferon gamma may cause the damage to enterocytes observed in this condition.
Assuntos
Gliadina/imunologia , Interferon gama/imunologia , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Anticorpos Monoclonais , Doença Celíaca/imunologia , Meios de Cultivo Condicionados/farmacologia , Citocinas/imunologia , Relação Dose-Resposta Imunológica , Feminino , Humanos , Imunidade Celular , Interferon gama/antagonistas & inibidores , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Masculino , Pessoa de Meia-Idade , Técnicas de Cultura de ÓrgãosRESUMO
BACKGROUND: A T-cell-mediated immune response may be responsible for the enteropathy seen in coeliac disease (CD), but it is unclear whether this is initiated in the epithelium or the lamina propria. We studied the site and number of cells expressing mRNA encoding the cytokines interleukin-2 (IL-2), IL-6, and tumour necrosis factor-alpha in jejunal biopsy specimens from patients with untreated or treated CD and normal controls. METHODS: Tissue sections were hybridized with 35S-labelled DNA oligonucleotide probes specific for each cytokine RNA sequence. Positive cells were counted in the lamina propria and epithelial compartments. RESULTS: For each cytokine significantly greater numbers of positive cells were found in the lamina propria of untreated CD patients. Few positive cells were detected in the epithelium of all three groups. CONCLUSIONS: This study shows that the immune response to gliadin appears to occur in the lamina propria and supports cell-mediated immunity in the pathogenesis of coeliac disease.
Assuntos
Doença Celíaca/metabolismo , Interleucina-2/biossíntese , Interleucina-6/biossíntese , Jejuno/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Biópsia , Estudos de Casos e Controles , Doença Celíaca/dietoterapia , Doença Celíaca/imunologia , Expressão Gênica , Glutens/administração & dosagem , Humanos , Hibridização In Situ , Interleucina-2/genética , Interleucina-6/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Pessoa de Meia-Idade , Sondas de Oligonucleotídeos , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
The levels of two pro-inflammatory cytokines, interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF-alpha), in coeliac disease were studied by immunohistochemistry. Jejunal biopsy specimens from patients with untreated disease, (n = 11), treated disease (n = 9), and normal controls, (n = 11) were stained to detect IL-6, TNF-alpha, CD45 (pan-leukocyte), and CD68 (macrophage surface antigen). Positive cells were identified in the epithelium (per 100 enterocytes) and in the lamina propria (per unit area). There was a significant increase in median IL-6 and TNF-alpha staining in both the lamina propria and the epithelium of untreated coeliac disease patients (lamina propria, 16.2 and 13.0 respectively; epithelium, 0.86 and 1.21, all p < 0.05) when compared with treated coeliac disease patients (lamina propria; 6.0 and 6.2, epithelium; 0.60 and 0.60) and controls (lamina propria; 6.5 and 7.5, epithelium; 0.58 and 0.60). A significant increase in the number of CD45 positive cells was found in the untreated coeliac disease lamina propria and epithelium (p < 0.05) but this was accompanied by a significant rise in CD68 positive cells in the lamina propria only (p < 0.05). Increased IL-6 and TNF-alpha in the lamina propria and epithelium of patients with untreated coeliac disease further supports their role in the immune pathogenesis of this disorder.
Assuntos
Doença Celíaca/imunologia , Interleucina-6/análise , Mucosa Intestinal/imunologia , Jejuno/imunologia , Fator de Necrose Tumoral alfa/análise , Adulto , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Doença Celíaca/tratamento farmacológico , Epitélio/imunologia , Feminino , Humanos , Imuno-Histoquímica , Antígenos Comuns de Leucócito/análise , Masculino , Pessoa de Meia-IdadeRESUMO
In situ hybridisation has been used to study interferon gamma (IFN gamma) mRNA expression in the small intestine of patients with coeliac disease. Sections of jejunal biopsies were obtained from five patients with treated and five with untreated coeliac disease and five disease controls. These sections were hybridised with radiolabelled specific DNA oligonucleotide probes. The lamina propria of untreated coeliac disease patients contained a significantly increased number of IFN gamma producing cells compared with controls but there was no significant difference between the coeliac patients treated with a gluten free diet and controls. The results suggest that IFN gamma may play a part in the immunopathogenesis of coeliac disease.