Diarrea vírica bovina: etiología, formas clínicas, distribución del virus y patogenia

El virus de la diarrea vírica bovina (vDVB) es un agente de distribución mundial y responsable de cuantiosas pérdidas económica a la cabaña bovina, estando clasificado dentro de la familia Flaviviridae junto a otros pestivirus como el virus de la peste porcina clásica, el virus de la enfermedad de la frontera de la oveja y el virus de la hepatitis C. Este virus se caracteriza por causar una amplia variedad de formas clínicas que van desde forma subagudas, que pasan desapercibidas, a formas caracterizadas por desarrollar una intensa leucopenia, trombocitopenia y hemorragias. Acorde con sus diferencias antigénicas y genéticas, los aislados del virus se pueden clasificar en 2 genotipos o especies: vDVB tipo 1 y vDVB tipo 2. El primero causa enfermedad leve pero en vacas preñadas, las infecciones fetales pueden inducir abortos y otras patologías reproductivas. El vDVB tipo 2 está asociado principalmente a la enfermedad respiratoria severa y a un cuadro hemorrágico agudo, caracterizado por trombocitopenia, diarrea hemorrágica, epistaxis, petequias, equimosis en mucosas, anemia, sangrado en zonas de inyección, pirexia, leucopenia y muerte.Independientemente del genotipo al que pertenezca, el vDVB puede ser clasificado en 2 biotipos acorde con su efecto sobre cultivos celulares: citopático (CP) y no citopático (NCP), siendo estos últimos los más comunes en la naturaleza. La infección del feto con cepas NCP entre los días 40 y 120 de la gestación, puede dar lugar al nacimiento de animales persistentemente infectados (PI). En estos animales el virus se distribuye ampliamente a través de todos los órganos, siendo el daño limitado, lo que permite que la gestación continúe. Estos animales están predispuestos a padecer infecciones secundarias, así como a desarrollar la denominada enfermedad de las mucosas cuando se infectan con cepas CP antigénicamente homólogas

Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesus leading to cirrhosis reversion in rats

Weinvestigated whether gene transfer of insulin-like growth factor I (IGF-I) to the hepatic tissue was able to improve liver histology and function in established liver cirrhosis. Rats with liver cirrhosis induced by carbon tetrachloride (CCl4) given orally for 8 weeks were injected through the hepatic artery with saline or with Simian virus 40 vectors encoding IGF-I (SVIGF-I), or luciferase (SVLuc). Animalsweresacrificed8weeksafter vector injection. In cirrhotic ratsweobserved that, whereas IGF-I was synthesized by hepatocytes, IGF-I receptor was predominantly expressed by nonparenchymal cells, mainly in fibrous septa surrounding hepatic nodules. Rats treated with SVIGF-I showed increased hepatic levels of IGF-I, improved liver function tests, and reduced fibrosis in association with diminished -smoothmuscle actin expression, up-regulation of matrix metalloproteases(MMPs)and decreased expression of the tissue inhibitors of MMPs TIM-1 and TIM-2. SVIGF-I therapy induced down-regulation of the profibrogenic molecules transforming growth factor beta (TGF ), amphiregulin, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and vascular endotheliumgrowthfactor(VEGF)andinduction of the antifibrogenicandcytoprotective hepatocyte growth factor (HGF). Furthermore, SVIGF-I-treated animals showed decreased expression of Wilms tumor-1 (WT-1; a nuclear factor involved in hepatocyte dedifferentiation) and up-regulation of hepatocyte nuclear factor 4 alpha (HNF4 ) (which stimulates hepatocellular differentiation). The therapeutic potential of SVIGF-I was also tested in rats with thioacetamide-induced liver cirrhosis. Also in this model, SVIGF-I improved liver function and reduced liver fibrosis in association with up-regulation of HGF and MMPs and down-regulation of tissue inhibitor of metalloproteinase 1 (TIMP-1). Conclusion: IGF-I gene transfer to cirrhotic livers induces MMPs and hepatoprotective factors leading to reversion of fibrosis and improvement of liver function. IGF-I gene therapy may be a useful alternative therapy for patients with advanced cirrhosis without timely access to liver transplantation

Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesus leading to cirrhosis reversion in rats

Weinvestigated whether gene transfer of insulin-like growth factor I (IGF-I) to the hepatic tissue was able to improve liver histology and function in established liver cirrhosis. Rats with liver cirrhosis induced by carbon tetrachloride (CCl4) given orally for 8 weeks were injected through the hepatic artery with saline or with Simian virus 40 vectors encoding IGF-I (SVIGF-I), or luciferase (SVLuc). Animalsweresacrificed8weeksafter vector injection. In cirrhotic ratsweobserved that, whereas IGF-I was synthesized by hepatocytes, IGF-I receptor was predominantly expressed by nonparenchymal cells, mainly in fibrous septa surrounding hepatic nodules. Rats treated with SVIGF-I showed increased hepatic levels of IGF-I, improved liver function tests, and reduced fibrosis in association with diminished -smoothmuscle actin expression, up-regulation of matrix metalloproteases(MMPs)and decreased expression of the tissue inhibitors of MMPs TIM-1 and TIM-2. SVIGF-I therapy induced down-regulation of the profibrogenic molecules transforming growth factor beta (TGF ), amphiregulin, platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), and vascular endotheliumgrowthfactor(VEGF)andinduction of the antifibrogenicandcytoprotective hepatocyte growth factor (HGF). Furthermore, SVIGF-I-treated animals showed decreased expression of Wilms tumor-1 (WT-1; a nuclear factor involved in hepatocyte dedifferentiation) and up-regulation of hepatocyte nuclear factor 4 alpha (HNF4 ) (which stimulates hepatocellular differentiation). The therapeutic potential of SVIGF-I was also tested in rats with thioacetamide-induced liver cirrhosis. Also in this model, SVIGF-I improved liver function and reduced liver fibrosis in association with up-regulation of HGF and MMPs and down-regulation of tissue inhibitor of metalloproteinase 1 (TIMP-1). Conclusion: IGF-I gene transfer to cirrhotic livers induces MMPs and hepatoprotective factors leading to reversion of fibrosis and improvement of liver function. IGF-I gene therapy may be a useful alternative therapy for patients with advanced cirrhosis without timely access to liver transplantation

Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ

BACKGROUND/AIMS: Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. METHODS: Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. RESULTS: CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. CONCLUSIONS: Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors

Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ

BACKGROUND/AIMS: Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. METHODS: Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. RESULTS: CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. CONCLUSIONS: Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors