INNATE INFLAMMATORY CELLS ARE NOT RESPONSIBLE FOR EARLY DEATH OF DONOR MYOBLASTS AFTER MYOBLAST TRANSFER THERAPY

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Abstract

Background.

Myoblast transfer therapy (MTT) is a cell-based gene therapy representing a potential treatment for Duchenne muscular dystrophy. The rapid disappearance of donor myoblasts from transplanted muscles after MTT is one of the most controversial and significant obstacles facing research in this area. Dystrophin-deficient muscles show constitutively high levels of inflammation, thus necessitating an examination of whether inflammatory cells, specifically natural killer (NK) cells, neutrophils, and macrophages, within dystrophic muscle are responsible for poor graft survival.

Methods.

Female mdx mice were treated with RB6–8C5 monoclonal antibody, PK136 monoclonal antibody, or clodronate liposomes to systemically deplete neutrophils, NK cells, and macrophages, respectively. After each depletion regimen, the mice and age-matched controls received 5.0×105 male myoblasts injected longitudinally into each tibialis anterior muscle. Donor myoblast survival was assessed by Y-chromosome specific quantitative real-time polymerase chain reaction analysis.

Results.

The systemic depletion of host neutrophils and NK cells resulted in a transient improvement in donor myoblast survival at 72 hr and 7 days post-MTT, respectively. Systemic depletion of macrophages had no significant beneficial effect on myoblast survival. Overall, the number of detectable male donor myoblasts was similar at time 0 and 1 hr post-MTT; however, there was significant loss by 24 hr (∼50%–70%) followed by a continual decline in donor cell numbers.

Conclusions.

Neutrophils and macrophages do not seem to play a major role in the rapid death of donor myoblasts after transplantation into dystrophic muscle. NK cells similarly seem to have no significant effect, contrary to earlier findings reported by our group.

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