INVESTIGADORES
PUNTEL Mariana
artículos
Título:
Immune-mediated Loss of Transgene Expression From Virally Transduced Brain Cells Is Irreversible, Mediated by IFNγ, Perforin, and TNFα, and due to the Elimination of Transduced Cells
Autor/es:
ZIRGER; PUNTEL; BERGERON; WIBOWO; MORIDZADEH; BONDALE; BARCIA; KROEGER; LIU; CASTRO; LOWENSTEIN
Revista:
MOLECULAR THERAPY (PRINT)
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2012 vol. 20 p. 808 - 819
ISSN:
1525-0016
Resumen:
The adaptive immune response to viral vectors reduces vector-mediated
transgene expression from the brain. It is unknown, however, whether
this loss is caused by functional downregulation of transgene expression
or death of transduced cells. Herein, we demonstrate that during the
elimination of transgene expression, the brain becomes infiltrated with
CD4+ and CD8+
T cells and that these T cells are necessary for transgene elimination.
Further, the loss of transgene-expressing brain cells fails to occur in
the absence of IFNγ, perforin, and TNFα
receptor. Two methods to induce severe immune suppression in immunized
animals also fail to restitute transgene expression, demonstrating the
irreversibility of this process. The need for cytotoxic molecules and
the irreversibility of the reduction in transgene expression suggested
to us that elimination of transduced cells is responsible for the loss
of transgene expression. A new experimental paradigm that discriminates
between downregulation of transgene expression and the elimination of
transduced cells demonstrates that transduced cells are lost from the
brain upon the induction of a specific antiviral immune response. We
conclude that the anti-adenoviral immune response reduces transgene
expression in the brain through loss of transduced cells.