Recombinant IL-12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung.
Enthusiasm for the use of recombinant adenoviruses in gene therapy has been tempered by the problematic immune responses that develop to the virus and virus-infected cells. Humoral immune responses to the input viral proteins generate neutralizing antibodies that thwart attempts to effectively administer the therapy more than once. Previous studies in murine models of gene therapy for cystic fibrosis (CF) have shown that the formation of adenoviral antibodies of the IgA subtype, a process that is dependent on T helper cells of the TH2 subset, contributes to a block in gene transfer that occurs following a second administration of virus. We show in this report that coadministration of interferon-gamma (IFN-gamma) (or interleukin-12, which activates TH1 cells to secrete IFN-gamma) with the recombinant adenovirus into the airway of C57BL/6 mice diminishes the activation of TH2 cells and formation of neutralizing antibody, allowing for efficient readministration of recombinant virus. This suggests a strategy for gene therapy of CF in which administration of a short-acting immune modulator at the time of gene therapy may be sufficient to overcome the problems of humoral immunity.
Yang
Y
Y
Institute for Human Gene Therapy, Wistar Institute, University of Pennsylvania Medical Center, Philadelphia 19104-4268, USA.
Trinchieri
G
G
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000914:Antibodies, Viral / Q000096:biosynthesis* / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D003673:Defective Viruses / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D015704:CD4 Antigens; D007070:Immunoglobulin A; D007155:Immunologic Factors; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma