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

Gene Therapy volume 16, pages 1380–1382 (2009)Cite this article

α-1 Antitrypsin (AAT) is a serine proteinase inhibitor secreted from hepatocytes and traversed to the lung, where it protects elastin from degradation by neutrophil elastase. Serum AAT concentration below 0.5 g l−1 (11 μM) can cause panacinar emphysema due to destruction of lung elastin fibers. AAT deficiency is the second-most common lung disease and accounts for 3% of all early deaths due to obstructive pulmonary disease.1

Given the limited treatment options for AAT deficiency, gene therapy represents a promising treatment for long-term correction of this metabolic disorder. Administration of vectors such as adeno-associated virus (AAV), adenovirus and helper-dependent adenovirus to the liver or muscle achieved stable therapeutic expression of human AAT (hAAT) in small and large animal models.1, 2, 3, 4, 5 Interestingly, no B cell response to the hAAT transgene product was detected in these studies. However, there is a considerable lack of information on the cytotoxic T lymphocyte (CTL) response to hAAT. The fact that hAAT expression is stable suggests that CTLs may either be absent or functionally impaired. Moreover, the hAAT protein itself may have tolerogenic immune properties, since it has recently been shown to induce tolerance to insulin-producing β cells in non-obese diabetic mice and to protect transplanted islet allografts from rejection through the induction of regulatory T cells.6, 7 These observations underscore the need to analyze the ensuing CTL response to hAAT and its modulation by gene transfer vectors, especially since AAV encoding hAAT is currently being pursued in human clinical trials.8

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  1. Department of Pathology and Laboratory Medicine, Gene Therapy Program, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    E Breous, S Somanathan & J M Wilson

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  1. E Breous
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  2. S Somanathan
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  3. J M Wilson
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Correspondence to J M Wilson.

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Breous, E., Somanathan, S. & Wilson, J. Identification of the immunodominant cytotoxic T-cell epitope of human -1 antitrypsin. Gene Ther 16, 1380–1382 (2009). https://doi.org/10.1038/gt.2009.100

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