title: Anti-dystrophin T cell responses in Duchenne muscular dystrophy: prevalence and a glucocorticoid treatment effect.
abstract: Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene transfer. In a trial of intramuscular adeno-associated virus (AAV)-mediated delivery of a therapeutic minidystrophin construct, we identified in two of six subjects the presence of a population of T cells that had been primed to recognize dystrophin epitopes before transgene delivery. As the presence of preexisting T cell immunity may have a significant effect on the success of therapeutic approaches for restoring dystrophin, we sought to determine the prevalence of such immunity within a DMD cohort from our Muscular Dystrophy Association clinic. Dystrophin-specific T cell immunity was evaluated in subjects with DMD who were either receiving the glucocorticoid steroid prednisone (n=24) or deflazacort (n=29), or who were not receiving steroids (n=17), as well as from normal age-matched control subjects (n=21). We demonstrate that increasing age correlates with an increased risk for the presence of anti-dystrophin T cell immunity, and that treatment with either corticosteroid decreases risk compared with no treatment, suggesting that steroid therapy in part may derive some of its benefit through modulation of T cell responses. The frequency of dystrophin-specific T cells detected by enzyme-linked immunospot assay was lower in subjects treated with deflazacort versus prednisone, despite similar overall corticosteroid exposure, suggesting that the effects of the two corticosteroids may not be identical in patients with DMD. T cells targeted epitopes upstream and downstream of the dystrophin gene mutation and involved the CD4⁺ helper and/or CD8⁺ cytotoxic subsets. Our data confirm the presence of preexisting circulating T cell immunity to dystrophin in a sizable proportion of patients with DMD, and emphasize the need to consider this in the design and interpretation of clinical gene therapy trials.
authors.affiliation: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH 43209, USA. Kevin.Flanigan@nationwidechildrens.org
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
authors.forename: Katie
authors.initials: K
authors.lastname: Campbell
authors.forename: Laurence
authors.initials: L
authors.lastname: Viollet
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gomez
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Walker
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
mesh_terms: D000367:Age Factors; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000276:immunology*; D011241:Prednisone / Q000627:therapeutic use; D011282:Pregnenediones / Q000627:therapeutic use
chemical_list: D016189:Dystrophin; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D011282:Pregnenediones; C021988:deflazacort; D011241:Prednisone