DYSTROPHIN ACTS AS A TRANSPLANTATION REJECTION ANTIGEN IN DYSTROPHIN-DEFICIENT MICE - IMPLICATION FOR GENE-THERAPY

Duchenne muscular dystrophy is a lethal and common X-linked recessive disease caused by a defect in dystrophin. Normal myoblast transplantat ion and dystrophin gene transfer have been expected to correct the def iciency in the muscles, but their clinical application has been hamper ed by the limited preservation of dystrophin-positive myofibers. In th is study we investigated the mechanism for immunologic rejection of no rmal C57BL/10 (B10) myoblasts transplanted into dystrophin-deficient m dr mice, an animal model of Duchenne muscular dystrophy, We found that mdr mice develop CTL specific for dystrophin itself, which were CDS d ominant and restricted by H-2K(b). We identified several antigenic pep tides derived from dystrophin that bind to H-2K(b) and are recognized by the mdr anti-B10 CTL. Immunologic tolerance against dystrophin was successfully induced by i.v. injection of these peptides before B10 my oblast transplantation, which resulted in sustained preservation of dy strophin-expressing myofibers in mdx mice. These results demonstrate t hat dystrophin is antigenic in dystrophin-deficient mice and that immu nologic regimen would be necessary to achieve the persistent expressio n of introduced dystrophin in the muscles of dystrophin-deficient indi viduals.