Immune responses to gene product of inducible promoters.
Efficient gene transfer has been achieved in several animal models using different vector systems, leading to stable transgene expression. The tight control of this expression is now an important outcome for the field of gene therapy. Such regulation is likely to be required for therapeutic applications and in some instances for safety reasons. For this purpose, several regulatable systems depending on small molecules have been developed. Among these, the tetracycline and the rapamycin dependent systems have been largely used. However, if long-term regulation of the transgene has been obtained in small animal models using these inducible systems, when translational studies were initiated in larger animals, the development of an immune response against proteins involved in transgene regulation were often observed. Such immune response was especially documented when using the TetOn tetracycline regulatable system in nonhuman primates (NHP). Humoral and destructive cellular immune responses against the transactivator involved in this regulation system were documented in a large majority of NHP leading to the complete loss of the transgene regulation and expression. This review will describe the immune responses observed in these different model systems applied for transgene regulation. Focus will be finally given on future directions in which such immune responses might be surmounted, enabling long-term transgene regulation in future clinical developments of gene transfer.
Le  Guiner
Caroline
C
INSERM U649, Université de Nantes, Faculté de Médecine, CHU-Hôtel Dieu, Bât J Monnet, 30 Boulevard J Monnet, 44035, Nantes Cedex 01, France. caroline.le-guiner@univ-nantes.fr
Stieger
Knut
K
Snyder
Richard O
RO
Rolling
Fabienne
F
Moullier
Philippe
P
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000917:Antibody Formation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D007166:Immunosuppressive Agents / Q000494:pharmacology; D023421:Models, Animal; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D012097:Repressor Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D015534:Trans-Activators / Q000494:pharmacology; D019076:Transgenes / Q000187:drug effects / Q000276:immunology*
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D012097:Repressor Proteins; D015534:Trans-Activators; C034811:tetracycline resistance-encoding transposon repressor protein; D013752:Tetracycline; D020123:Sirolimus