Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity.
Duchenne muscular dystrophy is a fatal, genetic disorder in which dystrophin-deficient muscle progressively degenerates, for which dystrophin gene transfer could provide effective treatment. The host immune response to dystrophin, however, is an obstacle to therapeutic gene expression. Understanding the dystrophin-induced host immune response will facilitate the discovery of strategies to prolong expression of recombinant dystrophin in dystrophic muscle. Using whole-body irradiation of the dystrophic mdx mouse before gene transfer, we temporally removed the immune system; a 600 rad dose removed peripheral immune cells, which were restored by self-reconstitution, and a 900 rad dose removed central and peripheral immune cells, which were restored by adoptive transfer of bone marrow from a syngeneic, dystrophin-normal donor. The anti-dystrophin humoral response was delayed and dystrophin expression was partially preserved in irradiated, vector-treated mice. Nonirradiated, vector-treated control mice lost muscle dystrophin expression completely, had an earlier anti-dystrophin humoral response and demonstrated muscle fibers focally surrounded with T cells. We conclude that dystrophin gene transfer induced anti-dystrophin humoral immunity and cell-mediated responses that were significantly diminished and delayed by temporal removal of the host central or peripheral immune cells. Furthermore, manipulation of central immunity altered the pattern of regulatory T cells in muscle.
Eghtesad
S
S
Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Zheng
H
H
Nakai
H
H
Epperly
M W
MW
Clemens
P R
PR
D000818:Animals; D018076:DNA, Complementary / Q000008:administration & dosage; D016189:Dystrophin / Q000235:genetics* / Q000276:immunology; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D056724:Immunity, Humoral / Q000528:radiation effects*; D051379:Mice; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000528:radiation effects; D014916:Whole-Body Irradiation
D018076:DNA, Complementary; D016189:Dystrophin
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