Identification of the immunodominant cytotoxic T-cell epitope of human -1 antitrypsin

Breous, Ekaterina; Somanathan, Suryanarayan; Wilson, James M.

doi:10.1038/gt.2009.100

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…Liver leukocytes or splenocytes from individual mice were added to wells at a density of 10 5 or 5×10 5 cells/well along with 2 μg/ml of hAAT CD8 T cell epitope [FALVNYIFF; described in (16)] or β-galactosidase CD8 T cell epitope [ICPMYARV; described in (17)]. Cells were incubated at 37° C, 5% CO 2 for 18 hours.…”

Section: Methodsmentioning

confidence: 99%

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver

et al. 2009

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The mechanisms of tolerance in the liver that limit susceptibility to food allergy and that mediate the acceptance of liver transplants even with a complete MHC mismatch remain poorly defined. Here we report that in a model of liver-directed gene transfer cytotoxic T lymphocyte (CTL) responses to non-self antigens are controlled by hepatic regulatory T cells (Tregs) that secrete the immunosuppressive cytokine interleukin (IL)-10 in response to the antigen. In addition, Kupffer cells (KCs), normally thought to initiate immune responses, are rendered tolerogenic in this context. The depletion of KCs results in a complete abrogation of IL-10 production by hepatic Tregs, indicating an interaction between Tregs and KCs in the induction of tolerance. Conclusion Our study suggests that hepatic Tregs together with KCs create a local suppressive microenvironment that prevents the establishment of the CTL response. These mechanisms provide pivotal insights and may prove instrumental in the tolerization toward non-self therapeutic proteins delivered to the liver.

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Section: Methodsmentioning

confidence: 99%

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver

et al. 2009

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“…Splenocytes from individual mice were added to wells at a density of 10 5 or 5 × 10 5 cells/well along with 2 μg/ml of β-gal CD8 T-cell epitope [ICPMYARV; described in 13 ], 2 μg/ml of AAT CD8 T-cell epitope [FALVNYIFF; described in 14 ] or an overlapping 15-mer peptide library spanning the full length Ad hexon divided into 4 (A, B, C and D) pools (Mimotopes, Victoria, Australia). Splenocytes were incubated at 37 °C, 5% CO 2 for 18 hours.…”

Section: Methodsmentioning

confidence: 99%

Inflammation Promotes the Loss of Adeno-Associated Virus–Mediated Transgene Expression in Mouse Liver

Breous¹,

Somanathan²,

Bell³

et al. 2011

Gastroenterology

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Background & Aims Transgenes delivered to livers of mice via adeno-associated virus (AAV) are expressed stably, via induction of immune tolerance. However, transgene expression is lost in higher-order primates. We investigated whether inflammatory processes, which likely differ between species, affect the stability of transgene expression. Methods We developed a mouse model of vector-unrelated, systemic inflammation following AAV-mediated transfer of genes to liver. Results Inflammation eliminated previously stable expression of trangenes delivered by AAV; the limited tissue destruction and persistence of AAV genomes implicated immune responses that were not mediated by cytotoxic T cells. Tumor necrosis factor (TNF)-α downregulated transgene expression from AAV, indicating a role for inflammatory cytokines in loss of transgene expression. Conclusions Inflammation and inflammatory cytokines such as TNF-α can reduce AAV-mediated expression of transgenes in livers of mice. Inflammation might therefore affect expression of transgenes from viral vectors in humans.

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BALB/c Mice Show Impaired Hepatic Tolerogenic Response Following AAV Gene Transfer to the Liver

2010

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Following adeno-associated virus (AAV) gene transfer to the liver, both C57BL/6 and BALB/c mice show long-term expression of nonself transgene antigens along with the absence of a transgene-specific immune response. However, in this study, we report that despite the equal ability to induce T-cell tolerance to vector-encoded antigens, the underlying mechanisms are entirely different in these two strains. We have previously shown that in C57BL/6 mice, cytotoxic T lymphocyte (CTL) responses to systemic AAV-delivered antigens are suppressed by combined actions of hepatic regulatory T cells (Tregs), Kupffer cells, and hepatic suppressive cytokines. In stark contrast, our present findings reveal that such tolerogenic response is not induced in the liver of BALB/c mice systemically administered with AAV. As a result, these mice fail to suppress a transgene-specific CTL response induced by a strong immunogenic challenge and express dramatically reduced levels of AAV-encoded antigen. Interestingly, there was active B-cell tolerance to the transgene antigen, which was mediated by splenic Tregs. We conclude that lack of tolerance induction in the liver renders BALB/c mice susceptible to CTL-mediated clearance of transduced hepatocytes.

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Identification of the immunodominant cytotoxic T-cell epitope of human -1 antitrypsin

Cited by 3 publications

References 12 publications

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver

Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver

Inflammation Promotes the Loss of Adeno-Associated Virus–Mediated Transgene Expression in Mouse Liver

BALB/c Mice Show Impaired Hepatic Tolerogenic Response Following AAV Gene Transfer to the Liver

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