Recombinant adenoviral vectors offer great promise for hepatic gene therapy because of the high efficiency of gene transfer into this target organ. Gene expression does not persist over the long term and secondary gene transfer is not possible because of a robust immunological response directed against the viral antigens, many of which are synthesized at low levels from vector transduced cells. We have obtained partial success in mice by 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 has several potential advantages over cytoablative therapy (1) 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 wildtype adenovirus. Using single-dose immunotherapy with soluble murine CTLA4Ig, we have obtained indefinite periods of adenovirus-mediated hepatic gene expression in mice. In our current study, we challenged M. fascicularis with recombinant adenoviral vectors with or without the co-administration of human CTLA4Ig (approved for phase 1 clinical trials). Our preliminary evidence suggests that humoral and cell-mediated immune responses directed against the vector are decreased with CTLA4Ig therapy. The relative persistence of adenoviral-mediated gene expression has been more difficult to determine because we have found that gene expression is more persistent in nonhuman primates than in mice and dogs. The administration of human CTLA4Ig to nonhuman primates resulted in a decreased lymphoctye proliferation in response to adenoviral vector administration but did not affect the persistence of expression of the trangene, human alpha 1-antitrypsin. For reasons that are not clear, gene expression persisted for several months with or without CTLA4Ig administration. At this time, we have decided to postpone future experiments until an optimal less antigenic adenoviral vector can be produced.
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