CHARACTERIZATION OF THE IMMUNE-RESPONSE AFTER LOCAL-DELIVERY OF RECOMBINANT ADENOVIRUS IN MURINE PANCREAS AND SUCCESSFUL STRATEGIES FOR READMINISTRATION

The pancreas is an ideal organ for adenoviral gene therapy because of the high level of gene transfer that can be achieved and because of th e many diseases that can potentially be treated using this technology. In this report, we characterize the immune response to direct pancrea tic injection of adenovirus and we overcome some of the limitations it imposes by using immunosuppression. Direct injection of recombinant a denovirus into the pancreas leads to the production of neutralizing an tibodies and to sensitized splenocytes which engage in increased cytot oxic, lymphoproliferative, and cytokine release activity when reexpose d to adenovirus. Transgene expression is transient and the vector cann ot be readministered. Deletion of CD4(+) T helper cells improves expre ssion over time (40% of pancreatic cells express transgene at day 28 v s. 5% in controls), and allows the vector to be readministered in the pancreas, albeit, inefficiently, when compared to naive animals. Simil arly, blockade of CD40 ligand, which preserves the CD4(+) T helper cel l population, also improves expression over time (30% of pancreatic ce lls express transgene at day 28), and allows the vector to be readmini stered. With both approaches, neutralizing antibodies are decreased an d the remaining splenocytes do not engage in activated immune response s. Thus, local delivery of the adenoviral vector induces a systemic re sponse that prevents pancreatic readministration, even with direct inj ection. Blockade of CD40 ligand and T helper cell depletion are transi ent regimens that induce systemic immunosuppression. Until the develop ment of newer strategies that selectively suppress adenoviral immune r esponses, these are viable alternatives for enhancement of pancreatic adenoviral delivery.