Recently, the genetic causes of a number of serious diseases affecting significant segments of the population have been determined. Many of these disorders have been shown to be due to a defect a single gene product. An extremely attractive potential therapy for disorders such as these is to introduce cDNA coding for the normal gene product into the abnormally functioning cells in the hopes that the pathologic phenotype can be reversed. While simple in principle, this type of """"""""gene therapy"""""""" is fraught with potential complications. In addition to the obvious problems of delivering the gene by the appropriate vector into the correct tissues and obtaining appropriately regulated levels of expression (questions addressed in the other projects of this program), a very real concern is the host response to the agent mediating the gene transfer. Vertebrate animals have evolved an extremely sophisticated immune system to protect against foreign invaders. In order for gene therapy to be successful, the vector mediating the introduction of new genetic material must evade the immune system sufficiently well to complement the existing defect. An additional potential complication is that for diseases such as cystic fibrosis which may be characterized by the absence of a protein, introduction of this protein may serve as an immunogen itself thus eliciting an """"""""autoimmune"""""""" response to cells successfully transfected. At this early stage of gene therapy,little is known about how various vectors stimulate an immune response at the level of B lymphocytes (humoral immunity), T lymphocytes (cell-mediated immunity), and Natural Killer cells (cytotoxicity in a non-major histocompatibility complex restricted fashion). In this proposal, we describe experiments to be performed in collaboration with the other projects of this program.
The specific aims of this project are to address in a systematic and prospective fashion the B cell, T cell, and NK cell responses to the introduction of the Ad2/CFTR- 1 vector in both human and simian hosts. The results of these experiments will form the initial data base for a description of the immunogenicity of this vector as well as provide information about potential causes should there be a failure of adequate expression of transferred cDNA in the human or simian subjects. This information will be essential for the development of the next generation of vectors designed to replace missing gene products in disorders such as CF.
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