(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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051807-02
Application #
2518568
Study Section
Special Emphasis Panel (SRC (06))
Program Officer
Mckeon, Catherine T
Project Start
1996-09-30
Project End
1998-08-31
Budget Start
1997-09-30
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195