Novel Model of Antigen-Specific Induction of Bile Duct Injury

Buxbaum, James; Qian, Peiqing; Khuu, Ciera; Shneider, Benjamin L.; Daikh, David I.; Gershwin, M. Eric; Allen, Paul M.; Peters, Marion G.

doi:10.1053/j.gastro.2006.10.020

Cited by 11 publications

(17 citation statements)

References 35 publications

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“…Besides NK lymphocytes, other effector cells (such as CD8 + cells) may also be required to carry out epithelial injury and obstruct the duct lumen (17). In this study, we found that CD8 + T cells infiltrated within the extrahepatic bile duct remnants in 95% of the cases with BA, suggesting that cytotoxic CD8 + T cells could mediate inflammatory infiltration of the duct wall.…”

Section: Discussionmentioning

confidence: 60%

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia

Guo

Zhu

et al. 2012

Pediatr Res

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Section: Discussionmentioning

confidence: 60%

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia

Guo

Zhu

et al. 2012

Pediatr Res

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“…Adoptively transfer of these naïve antigen-specific T cells, induced liver targeted inflammation. These reagents have been utilized to study biliary directed inflammation in transgenic mice with OVA expressed on biliary epithelial cells [5].…”

Section: Discussionmentioning

confidence: 99%

“…Livers were perfused with collagenase (0.1 mg/mL in PBS: Sigma, St Louis, MO) via the portal vein and mononuclear cells (MNC) isolated as described [5] on a discontinuous percoll gradient. The interface contained mononuclear >95% CD45 positive by flow cytometry.…”

Section: Hepatic Mononuclear Cells Isolation and Facs Analysesmentioning

confidence: 99%

“…MNC were labeled for 45 minutes with fluorescein (FITC), phycoerythrin (PE), PE-Cy5.5, and APC conjugated mAb to MNC (CD45), T lymphocytes (CD3, CD4, and CD8), TCR Vα2, Thy 1.1 and Thy 1.2. They were subsequently washed with FACS buffer and analyzed by flow cytometry as described [5].…”

Section: Hepatic Mononuclear Cells Isolation and Facs Analysesmentioning

confidence: 99%

“…Cell division in vivo was measured by labeling OT-I and OT-II splenoctyes with carboxyfluorescein diacetate succinimidyl ester (CFSE) (Molecular Probes, Eugene, OR) as described [5]. Briefly, OT-I or OT-II spleen cells at a concentration of 2 × 10 7 cells/cc were labeled with CFSE in DMSO (1 mg/cc) for 5 minutes at 37° C. The reaction was quenched with 10% FBS/RPMI, washed, confirmed to be > 99% CFSE labeled by flow cytometry, and injected into OVA-HEP mice.…”

Section: Hepatic Mononuclear Cells Isolation and Facs Analysesmentioning

confidence: 99%

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Hepatitis resulting from liver-specific expression and recognition of self-antigen

Buxbaum

Qian

Allen

et al. 2008

Journal of Autoimmunity

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Liver-specific immune reactivity in response to aberrant expression of antigen on the surface of hepatocytes is thought to be a major factor in development of autoimmune hepatitis (AIH). Persistent inflammation develops when these antigens are not eliminated and/or responses are not appropriately regulated. We have developed transgenic mice (OVA-HEP), which express chicken ovalbumin on the surface of hepatocytes. These mice are tolerant to ovalbumin, develop normally and have shown no evidence of liver or other disease up to 2 years of age. Adoptive transfer of naïve ovalbumin specific T cells into OVA-HEP transgenic mice led to liver specific inflammation in a dose dependent manner. This hepatic necroinflammation was dependent upon CD8+ Vα2 OVA specific T cells; was limited to the liver; and was augmented by OVA-specific CD4+ T cell help; but did not result from adoptive transfer of ovalbumin specific CD4 T cells alone. The response was self limited but persistent inflammation developed after repeated transfer of antigen specific T cells. This model of T cell recognition of antigen on hepatocytes may be used to understand many liver-specific aspects of the immune response in autoimmune hepatitis.

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Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis

et al. 2007

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The pathogenesis of autoimmune liver diseases is poorly understood. Animal models are necessary to investigate antigen presentation and priming of T-cells in the context of autoimmunity in the liver. Transgenic mouse models were generated in which the model antigen ovalbumin is expressed in hepatocytes (TF-OVA) or cholangiocytes (ASBT-OVA). A utoimmune hepatitis and cholangitis are triggered by autoreactive T-cells. Animal models are needed to study the early events in their pathogenesis, namely, the priming of autoreactive T-cells. The requirements for an immune-based animal model are restriction of the immune response to the liver, antigen specificity, and the potential to study the priming of CD8 and CD4 T-cells. Several animal models of autoimmune hepatitis have been developed, 1 none of which fulfills these criteria. Transgenic expression of foreign major histocompatibility complex (MHC) class I molecules in the liver has been widely used. [2][3][4] However, this model has a significant disadvantage: unlike the pathophysiology of an immune or autoimmune reaction, CD8 T cells recognize their antigen on hepatocytes but the antigen is not presented by professional antigen-presenting cells (APCs) in this model. Injection of the synthetic peptide ova p257-264 (SIINFEKL) into mice followed by transfer of antigenspecific CD8 T-cells has also been used, 5 but the possibility of peptide binding to MHC-I molecules on T-cells themselves and their activation by each other 6 or by unrelated cells is a possible concern. Infection with virus expressing ovalbumin 7 results in temporary expression of ovalbumin but also activation of innate immune mechanisms. No animal model exists that allows the simulta-

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Novel Model of Antigen-Specific Induction of Bile Duct Injury

Abstract: Background & Aims-Biliary-directed inflammation is an important cause of acute and chronic liver disease. We developed and characterized a transgenic mouse model of immunemediated hepatobiliary injury.

Cited by 11 publications

References 35 publications

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia

Hepatitis resulting from liver-specific expression and recognition of self-antigen

Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis

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