Journal
MOLECULAR THERAPY
Volume 21, Issue 8, Pages 1592-1601Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2013.105
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Funding
- Dutch Diabetes Research Funds [DFN 2005.00.0212, DFN 2007.00.0015, 2008.40.001]
- UK Department of Health via the National Institute for Health Research Biomedical Research Centre Award
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
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Islet transplantation is a promising therapy for type 1 diabetes, but graft function and survival are compromised by recurrent islet autoimmunity. Immunoprotection of islets will be required to improve clinical outcome. We engineered human beta cells to express herpesvirus-encoded immune-evasion proteins, immunevasins. The capacity of immunevasins to protect beta cells from autoreactive T-cell killing was evaluated in vitro and in vivo in humanized mice. Lentiviral vectors were used for efficient genetic modification of primary human beta cells without impairing their function. Using a novel beta-cell-specific reporter gene assay, we show that autoreactive cytotoxic CD8(+) T-cell clones isolated from patients with recent onset diabetes selectively destroyed human beta cells, and that coexpression of the human cytomegalovirus-encoded US2 protein and serine proteinase inhibitor 9 offers highly efficient protection in vitro. Moreover, coimplantation of these genetically modified pseudoislets with beta-cell-specific cytotoxic T cells into immunodeficient mice achieves preserved human insulin production and C-peptide secretion. Collectively, our data provide proof of concept that human beta cells can be efficiently genetically modified to provide protection from killing mediated by autoreactive T cells and retain their function in vitro and in vivo.
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