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Gastroenterology ; 143(5): 1361-1374, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22863765

RESUMO

BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. METHODS: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and ß specifically in acinar cells (Ela1-LTab mice). RESULTS: Messenger RNA levels of LTα and ß were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαß (Ela1-LTαß) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαß did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTßR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS: Overexpression of LTαß specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTßR ligands might be used to treat patients with AIP.


Assuntos
Doenças Autoimunes/metabolismo , Receptor beta de Linfotoxina/metabolismo , Pancreatite Crônica/imunologia , Pancreatite Crônica/metabolismo , Transdução de Sinais , Células Acinares/metabolismo , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Análise de Variância , Animais , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/tratamento farmacológico , Estudos de Casos e Controles , Células Cultivadas , Quimiocinas/efeitos dos fármacos , Quimiocinas/metabolismo , Modelos Animais de Doenças , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Contagem de Linfócitos , Receptor beta de Linfotoxina/sangue , Linfotoxina-alfa/efeitos dos fármacos , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-beta/efeitos dos fármacos , Linfotoxina-beta/genética , Linfotoxina-beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Elastase Pancreática/genética , Elastase Pancreática/metabolismo , Pancreatite Crônica/sangue , Pancreatite Crônica/tratamento farmacológico , Regiões Promotoras Genéticas , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Estatísticas não Paramétricas , Subpopulações de Linfócitos T , Regulação para Cima
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