Human Molecular Genetics, Vol 5, 1703-1712, Copyright © 1996 by Oxford University Press
Y Yang, SE Haecker, Q Su and JM Wilson
Skeletal muscle is an attractive target for somatic gene transfer of both
acquired and inherited disorders. Direct injection of adenoviral vectors in
the skeletal muscle leads to recombinant gene expression in a large number
of muscle fibers. Transgene expression has been transient in most organs
and associated with substantial inflammation when experiments are performed
in adult immune competent mice. In this report, we utilize a variety of in
vivo and in vitro models of T and B cell function to characterize the
nature of the immune response to adenoviral vectors injected into murine
skeletal muscle. Cellular immunity dependent on CD4+ and CD8+ T cells
contributes to the loss of recombinant gene expression and the development
of localized inflammation. Antigen specific activation of T cells occurs to
both viral proteins and the reporter gene beta-galactosidase. Systemic
levels of neutralizing antibody to the capsid proteins of the vector are
also generated. Destructive immune responses responsible for loss of
transgene expression are largely directed against beta-galactosidase in
that transgene expression was stable when beta-galactosidase was eliminated
as a neoantigen in mice transgenic for lacZ. A strategy to prevent the
cellular and humoral immunity to this therapy was developed based on
transiently ablating CD4+ T cell activation at the time of vector delivery.
Encouraging results were obtained when vector was administered with one of
several immune modulating agents including cyclophosphamide, mAb to CD4+
cells, and mAb to CD40 ligand. These studies indicate that cellular and
humoral immune responses are elicited in the context of gene therapy
directed to skeletal muscle with adenoviral vectors. Transient ablation of
CD4+ T cell activation prevents the effects responses of the CD8+ T and B
cells.
ARTICLES
Immunology of gene therapy with adenoviral vectors in mouse skeletal muscle
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
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