Genetically engineered human islets protected from CD8-mediated autoimmune destruction in vivo.
Mol Ther
; 21(8): 1592-601, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23689598
ABSTRACT
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 ß cells to express herpesvirus-encoded immune-evasion proteins, "immunevasins." The capacity of immunevasins to protect ß 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 ß cells without impairing their function. Using a novel ß-cell-specific reporter gene assay, we show that autoreactive cytotoxic CD8(+) T-cell clones isolated from patients with recent onset diabetes selectively destroyed human ß 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 ß-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 ß 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Autoimunidade
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Transplante das Ilhotas Pancreáticas
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Ilhotas Pancreáticas
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Linfócitos T CD8-Positivos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article