Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mucosal Immunol ; 10(4): 971-982, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27848951

RESUMO

Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.


Assuntos
Colite/genética , Doença de Crohn/genética , Ileíte/genética , Mucosa Intestinal/patologia , Microbiota/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Colite/induzido quimicamente , Colite/microbiologia , Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Suscetibilidade a Doenças , Disbiose , Fezes/microbiologia , Humanos , Ileíte/imunologia , Ileíte/microbiologia , Camundongos , Camundongos Knockout , Camundongos Mutantes , Proteína Adaptadora de Sinalização NOD2/genética , RNA Ribossômico 16S/análise , Receptores de Reconhecimento de Padrão/genética , Fator de Transcrição STAT6/metabolismo
2.
Clin Pharmacol Ther ; 97(1): 22-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25670380

RESUMO

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disease of the intestine that includes both Crohn's disease and ulcerative colitis, and afflicts nearly 1 million people throughout North America. As our understanding of IBD pathogenesis grows, several new therapies have been developed that use monoclonal antibodies to specifically target key mediators and biological pathways implicated in IBD immune dysfunction. One important pathway involves leukocyte trafficking and infiltration into the affected intestinal tissues. This review provides a summary of the different therapies that have been developed to inhibit leukocyte trafficking to the inflamed gut, and evaluates the relative safety and efficacy of these novel drugs within the context of existing medical therapies for IBD.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Movimento Celular/efeitos dos fármacos , Colite Ulcerativa/imunologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/imunologia , Doença de Crohn/fisiopatologia , Desenho de Fármacos , Humanos , Leucócitos/metabolismo , Terapia de Alvo Molecular
3.
Mucosal Immunol ; 6(2): 267-75, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22785225

RESUMO

Although regulatory T cells (Tregs) have been implicated in inflammatory bowel disease, Tregs from Crohn's disease (CD) patients are increased in number and function normally in vitro. To clarify this disparity, we studied Treg function in vivo using a spontaneous model of CD-like ileitis. We first administered anti-CD25-depleting antibodies to SAMP1/YitFc (SAMP) mice to assess ileitis; mesenteric lymph node cells were then transferred into SCID (severe combined immunodeficient) recipients to induce colitis. CD25 depletion increased the severity of both spontaneous ileitis and adoptively transferred colitis. Interestingly, a second transfer of CD4(+)CD25(+) cells from untreated AKR control mice was able to ameliorate the induced colitis, whereas CD4(+)CD25(+) cells from untreated SAMP mice were not, suggesting a functional abnormality in SAMP Tregs. Anti-CD25 treatment in SAMP mice also induced proliferation of CD25(-)Foxp3(+) Tregs, which had a proinflammatory intestinal T helper type 1/ T helper type 2 (Th1/Th2) effector phenotype. These studies demonstrate Treg dysfunction in a spontaneous model of CD-like ileitis.


Assuntos
Doença de Crohn/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Doença de Crohn/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Depleção Linfocítica , Camundongos , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Fatores de Tempo
5.
J Biol Chem ; 276(47): 43713-22, 2001 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-11559712

RESUMO

We reported previously that human colonic epithelial cells produce the C-X-C chemokine epithelial neutrophil-activating peptide-78 (ENA-78) and that its expression is up-regulated in ulcerative colitis. The aim of this study was to investigate the transcriptional regulation of ENA-78 gene expression in Caco-2 intestinal epithelial cells. Reporter gene transfection and electrophoretic mobility shift assay studies demonstrated that cooperation between two regions of the ENA-78 promoter were required for maximal gene expression in interleukin-1beta-stimulated Caco-2 cells. Binding of activated p50/p65 nuclear factor-kappaB to nucleotides -82 to -91 was essential for interleukin-1beta-dependent gene transcription, whereas binding of constitutively expressed zinc-requiring nuclear factors to nucleotides -125 to -134 (site A) was required for basal gene expression. Scanning mutagenesis of site A demonstrated overlapping binding elements at this locus. One site (CTCCCCC) bound Sp1 and Sp3, and overexpression of Sp1 (but not Sp3) up-regulated basal ENA-78 transcription. Another site (CCCCTCCCCC) was found to bind the zinc finger nuclear factor ZBP-89, and overexpression of this protein significantly repressed ENA-78 reporter gene activity. This study demonstrates that ENA-78 gene expression in Caco-2 intestinal epithelial cells is subject to complex regulation involving the coordinate binding of ZBP-89, Sp1, and nuclear factor-kappaB to the ENA-78 promoter.


Assuntos
Quimiocinas CXC , Colo/metabolismo , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica/fisiologia , Interleucina-8/análogos & derivados , Interleucina-8/genética , NF-kappa B/fisiologia , Fator de Transcrição Sp1/fisiologia , Fatores de Transcrição/fisiologia , Transcrição Gênica/fisiologia , Animais , Sítios de Ligação , Células CACO-2 , Quimiocina CXCL5 , Drosophila , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/genética , Genes Reporter , Humanos , Luciferases/genética , Regiões Promotoras Genéticas , Fator de Transcrição Sp1/genética , Zinco/metabolismo
6.
Inflamm Bowel Dis ; 7(2): 106-12, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11383582

RESUMO

An association may exist between Crohn's disease (CD) and lymphoid/myeloid malignancies. We aimed to evaluate the 2-year cumulative incidence rate of lymphoid/myeloid malignancy among hospitalized CD patients. This is a retrospective cohort study using hospital discharge data from California and Virginia. Cohorts were defined by the presence or absence of a CD diagnosis in all patients discharged during a single calendar year (Year-2). The presence or absence of lymphoid/myeloid malignancy was determined for all hospitalizations during a 4-year period (Year-1 to Year-4) for each member of both cohorts. To obtain a 2-year cumulative incidence rate, patients with lymphoid/myeloid malignancy prior to or at the time of their first admission in Year-2 were excluded. Patients were followed for 8 quarters after this admission for the incidence of lymphoid/myeloid malignancy. Cumulative incidence rates and odds ratios were calculated. The crude 2-year incidence rate of lymphoid/myeloid malignancy among hospitalized CD patients was 3.87/1.000 CD patients (21/5,426; 95% CI = 2.40-5.92). The odds ratio adjusted for age, gender, and race was 2.04 (95% CI = 1.33-3.14, p < 0.001). The 2-year cumulative incidence of lymphoid/myeloid malignancies among hospitalized CD patients is greater than that seen in hospitalized patients without CD. This finding supports the need for further prospective population-based studies.


Assuntos
Doença de Crohn/complicações , Leucemia/complicações , Linfoma/complicações , Mieloma Múltiplo/complicações , Fatores Etários , Estudos de Coortes , Doença de Crohn/epidemiologia , Interpretação Estatística de Dados , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Leucemia/epidemiologia , Linfoma/epidemiologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Razão de Chances , Estudos Retrospectivos
7.
Gastroenterology ; 120(7): 1640-56, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11375946

RESUMO

BACKGROUND & AIMS: The cost-utility of infliximab is unknown. The aim of this study was to determine the incremental cost-utility (CU(inc)) of medical therapy for Crohn's disease (CD) perianal fistula. METHODS: A Markov model was used to simulate a 1-year treatment period with the following: 6-mercaptopurine and metronidazole [6MP/met] (comparator), 3 infliximab infusions + 6MP/met as second-line therapy (intervention I), infliximab with episodic reinfusion (intervention II), and 6MP/met + infliximab as second-line therapy (intervention III). Utilities were elicited from patients with CD and healthy individuals by standard gamble, and costs were obtained from hospital billing data. Uncertainty was assessed by sensitivity analysis. RESULTS: All strategies had similar effectiveness. Interventions I, II, and III were slightly more effective, but also more costly than 6MP/met (Intervention I: CU(inc) = $355,450/quality-adjusted life-years [QALY]; Intervention II: CU(inc) = $360,900/QALY; Intervention III: CU(inc) = $377,000/QALY). If the cost of infliximab were reduced to $304 per infusion, the CU(inc) for intervention II would be $54,050/QALY. CONCLUSIONS: Based on available data, all strategies had similar effectiveness in our model, but infliximab was much more expensive than 6MP/met. The incremental benefit of infliximab for treating CD perianal fistulae over a 1-year period may not justify the higher cost. Prospective studies directly comparing 6MP/met and infliximab are warranted.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Fístula Retal/tratamento farmacológico , Adulto , Custos de Medicamentos , Quimioterapia Combinada , Feminino , Custos de Cuidados de Saúde , Humanos , Infliximab , Masculino , Mercaptopurina/administração & dosagem , Metronidazol/administração & dosagem , Pessoa de Meia-Idade
8.
Gastroenterology ; 119(4): 972-82, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11040184

RESUMO

BACKGROUND & AIMS: Interleukin (IL)-16 is a T lymphocyte- derived cytokine that uses CD4 as its receptor and hence selectively recruits CD4-bearing cells. Infiltrating CD4(+) T cells are a feature of Crohn's disease; however, the role of IL-16 in intestinal inflammation is unknown. The aim of this study was to determine whether IL-16 production is increased in inflammatory bowel disease and whether IL-16 participates in trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. METHODS: IL-16 messenger RNA and protein levels in inflammatory bowel disease tissues were determined by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. C57BL/6 or BALB/c mice were treated with vehicle, TNBS alone, TNBS + anti-IL-16 monoclonal antibody (mAb), TNBS + control mAb, or were untreated. Colonic injury and inflammation were evaluated after 3 or 10 days. RESULTS: Colonic IL-16 protein levels were increased in patients with Crohn's disease (P<0.05) but not ulcerative colitis. Anti-IL-16 mAb treatment significantly reduced TNBS-induced weight loss (P< 0.001), mucosal ulceration (P<0.05), myeloperoxidase activity (P< 0.001), and TNBS-mediated increases in mucosal levels of IL-1beta (P<0.05) and tumor necrosis factor alpha (P<0.01). CONCLUSIONS: Anti-IL-16 mAb reduced colonic injury and inflammation induced by TNBS in mice. Colonic mucosal IL-16 levels were elevated in Crohn's disease, suggesting a role for IL-16 in the pathophysiology of inflammatory bowel disease.


Assuntos
Colite/genética , Colo/imunologia , Doença de Crohn/genética , Regulação da Expressão Gênica , Interleucina-16/genética , Mucosa Intestinal/imunologia , Transcrição Gênica , Animais , Anticorpos Monoclonais/uso terapêutico , Colite/induzido quimicamente , Colite/imunologia , Colite/terapia , Colo/patologia , Doença de Crohn/imunologia , Doença de Crohn/patologia , Modelos Animais de Doenças , Humanos , Interleucina-16/análise , Interleucina-16/imunologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Trinitrobenzenossulfônico
9.
Am J Physiol Gastrointest Liver Physiol ; 278(5): G665-9, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10801257

RESUMO

Crohn's Disease (CD) affects more than 500,000 individuals in the United States and represents the second most common chronic inflammatory disorder after rheumatoid arthritis. Although major advances have been made in defining the basic mechanisms underlying chronic intestinal inflammation, the precise etiopathogenesis of CD remains unknown. We have recently characterized two novel mouse models of enteritis that express a CD-like phenotype, namely the TNF DeltaARE model of tumor necrosis factor (TNF) overexpression and the SAMP1/Yit model of spontaneous ileitis. The unique feature of these models is that they closely resemble CD for location and histopathology. These genetically manipulated new models of intestinal inflammation offer a powerful tool to investigate potential causes of human disease and may allow the development of novel disease-modifying therapeutic modalities for the treatment of CD.


Assuntos
Doença de Crohn/genética , Doença de Crohn/fisiopatologia , Fator de Necrose Tumoral alfa/genética , Animais , Doença de Crohn/patologia , Modelos Animais de Doenças , Humanos , Ileíte/genética , Ileíte/fisiopatologia , Camundongos , Camundongos Mutantes , Camundongos Transgênicos
10.
Curr Opin Gastroenterol ; 16(4): 310-7, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17031094

RESUMO

The precise cause of inflammatory bowel disease remains unclear. Relevant animal models are important tools for studying the underlying mechanisms of inflammation and disease pathogenesis. The purpose of this review is to summarize the various types of animal models available for use in inflammatory bowel disease research and to illustrate how these models have contributed to a better understanding of the etiopathogenesis of inflammatory bowel disease, particularly focusing on papers published during calendar year 1999. Studies using appropriate animal models have provided important discoveries in this field of investigation. These include determination of the key role that pathogenic and regulatory T cells, proinflammatory and immunoregulatory cytokines, indigenous bacterial flora, and putative predisposing genes play in the disease process. The availability of new animal models that closely resemble the human disease is expected to allow further characterization of the initiating event(s) in inflammatory bowel disease and lead to a possible cure for this devastating disease.

11.
Gastroenterology ; 117(6): 1433-7, 1999 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-10579985

RESUMO

The relationship between chronic inflammatory conditions and malignancy is complex. We describe the clinical course of 2 patients with Crohn's disease (CD) in whom lymphoma was diagnosed after treatment with infliximab. The first patient was a 61-year-old man with a 30-year history of fistulizing CD in whom B-cell non-Hodgkin's lymphoma was diagnosed 9 months after treatment with infliximab. The second is a 29-year-old man with CD in whom nodular sclerosing Hodgkin's lymphoma was diagnosed 3 weeks after infusion with infliximab. The lymphoma presented with pleural effusions, mediastinal and cervical adenopathy, and no gastrointestinal lesion. We describe the implications of these cases for the use of immunomodulatory therapy in CD and the questionable association between CD and lymphoma.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Doença de Crohn/complicações , Fármacos Gastrointestinais/efeitos adversos , Linfoma/induzido quimicamente , Adulto , Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab , Linfoma/complicações , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...