title: Prediction of cellular immune responses against CFTR in patients with cystic fibrosis after gene therapy.
abstract: Different classes of mutations (class I-VI) of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene are responsible for lung/pancreatic disease. The most common mutation, DeltaF508, is characterized by expression of precursor forms of CFTR but no functional CFTR. Since only 5-10% of normal CFTR function is required to correct the electrophysiologic defect across the airway epithelium, gene therapy holds promise for treatment of patients with CF lung disease. However, efficient delivery and transgene expression are not the only parameters that may influence the success of gene therapy. Host-specific immune responses generated against the therapeutic CFTR protein may pose a problem, especially when the coding sequence between the normal CFTR and mutated CFTR differ. This phenomenon is more pertinent to class I mutations in which large fragments of the protein are not expressed. However, T cells directed against epitopes that span sequences containing class II-V mutations are also possible. We used MHC-binding prediction programs to predict the probability of cellular immune responses that may be generated against CFTR in DeltaF508 homozygote patients. Results obtained from running the prediction algorithms yielded a few high-scoring MHC-Class I binders within the specific sequences, suggesting that there is a possibility of the host to mount a cellular immune response against CFTR, even when the difference between therapeutic and host CFTR is a single amino acid (F) at position 508.
authors.affiliation: Gene Therapy Program, Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine, University of Pennsylvania, Philadelphia, PA 19104-3403, USA.
authors.forename: Joanita
authors.initials: J
authors.lastname: Figueredo
authors.forename: Maria P
authors.initials: MP
authors.lastname: Limberis
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D003550:Cystic Fibrosis / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000276:immunology*; D015316:Genetic Therapy; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding
chemical_list: D015395:Histocompatibility Antigens Class I; D010455:Peptides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator