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Prediction of Cellular Immune Responses against CFTR in Patients with Cystic Fibrosis after Gene Therapy

Gene Therapy Program, Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to James M. Wilson, M.D., Ph.D., 125 S. 31st Street, TRL, Suite 2000, Philadelphia, PA 19104-3403. E-mail: wilsonjm{at}mail.med.upenn.edu

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, F508, 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 F508 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.

Key Words: MHC ligand • CFTR • gene therapy • F508

CLINICAL RELEVANCE These findings suggest that there is a strong possibility of a recipient of gene therapy to mount an immune response toward the therapeutic gene product. Immune modulation would then be required to improve the success rate of long-term gene therapy.