(Taken directly from the application) The excitement of using recombinant adenovirus vectors for the treatment of cystic fibrosis has been hindered by the resulting immunologic response of the host to the vector and vector transduced cells. General long-term immunosuppressive therapy using standard agents, such as cyclosporin, have not been successful in inhibiting immune mediated clearance of expression. Although some success has been achieved using cytoablative therapy, this approach results in systemic-side effects and is broadly immunosuppressive. We have sought and obtained partial success in modifying the host response to enhance gene expression, by selectively blocking the interactions of costimulatory ligands on T lymphocytes and antigen presenting cells (APC), which play an important role in the initiation of an effective. antigen-specific. immunologic response. Blockade of the costimulatory interactions between CD28 on T cells with B7-1,-2 on APC using soluble CTLA4Ig and of the interaction of CD40 on APC with its ligand on T cells using anti-CD40 ligand mAb has several potential advantages over cytoablative therapy: (l) it results in transient immunosuppression, (2) it is not cytoablative and does not affect other cells (e.g., neutrophils) involved in innate immune responses. (3) it has minimal effect on pre-existing immunity and (4) it is unlikely to result in immunological tolerance to wild type adenovirus. We plan to use the results from our initial studies as a starting point to determine whether or not these agents, can safely circumvent immune-mediated limitations to adenoviral-mediated gene therapy. Specifically, we plan to study persistence of liver and pulmonary gene expression, and the host immunological response to mice receiving either first or advanced generation adenovirus vectors with or without combinations of soluble or vector expressed CTLA4Ig/ anti2CD40 ligand. These studies should reveal important information as to the future of using recombinant adenovirus vectors for gene therapy for cystic fibrosis.
