title: Self-reactive CFTR T cells in humans: implications for gene therapy.
abstract: Cystic fibrosis (CF) is one of the most common autosomal recessive lethal disorders affecting white populations of northern European ancestry. To date there is no cure for CF. Life-long treatments for CF are being developed and include gene therapy and the use of small-molecule drugs designed to target specific cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. Irrespective of the type of molecular therapy for CF, which may include gene replacement, exon skipping, nonsense suppression, or molecular correctors, because all of these modulate gene expression there is an inherent risk of activation of T cells against the wild-type version of CFTR. Here we report the validation of the human interferon-γ enzyme-linked immunospot assay and its application for the analysis of CFTR-specific T cell responses in patients with CF and in non-CF subjects. We found non-CF subjects with low levels of self-reactive CFTR-specific T cells in the United States and several patients with CF with low to high levels of self-reactive CFTR-specific T cells in both the United States and the United Kingdom.
authors.affiliation: 1 Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania , Philadelphia, PA 19104.
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.forename: Uta
authors.initials: U
authors.lastname: Griesenbach
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dorgan
authors.forename: Samia
authors.initials: S
authors.lastname: Soussi
authors.forename: A Christopher
authors.initials: AC
authors.lastname: Boyd
authors.forename: Jane C
authors.initials: JC
authors.lastname: Davies
authors.forename: Tracy E
authors.initials: TE
authors.lastname: Higgins
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Hyde
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Gill
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Innes
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Eric W
authors.initials: EW
authors.lastname: Alton
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Maria P
authors.initials: MP
authors.lastname: Limberis
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015551:Autoimmunity; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D059425:Interferon-gamma Release Tests / Q000379:methods*; D008297:Male; D051379:Mice; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007371:Interferon-gamma