CELLULAR TRANSPLANTATION IN GENETICALLY MODULATED LIVER

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DESCRIPTION: Somatic modulation of the liver using gene transfer technology is a technique which allows testing of hypotheses with potential application in the transplant setting. In this context, the investigators propose that the immune milieu can be modified if livers are transduced with sequences expressing proteins/peptides capable of suppressing the immune response. In theory, genetically modified liver could serve as an "immunologically protected site," able to accept allogeneic cell transplantation without rejection. In this model, inhibition of the immune response within the native liver would be accomplished by expression of proteins/peptides capable of inhibiting T cell recognition (non-polymorphic MHC peptides), activity (viral IL-10), or costimulatory pathways (CTLA4lg). To test this hypothesis the proposal has three specific aims: 1) To apply recent and future developments in gene transfer technology for modulation of the liver as it is prepared to be a site for cellular transplantation. The use of novel adenovirus vector constructs allow correlation of variables unique to the transplant setting: optimal length of expression, immune response against transduced liver cells, the impact of recombinant inhibitor protein/peptide production on the life span of the transferred sequences, and the ability to restrict vector expression to the liver; 2) To follow the biological function and determine conditions which promote survival of transplanted allogeneic hepatocytes in the modulated native liver. The experiments will be performed in clinically-relevant models of liver-related protein deficiency, and will correlate vector expression, biological function of the transplanted cells, and alloimmune response; 3) The application of gene transfer technology in the transplant setting must consider the potential consequences of suppressing immune processes outside the transduced organ. These studies attempt to define the relationship between systemic immunity and site-specific suppression of the alloimmune response, and to correlate short or long term expression of immunosuppressive proteins/peptides with rejection, preservation of extrahepatic T cell response to nominal antigen, and maintenance of immune-surveillance of syngeneic tumors. The ultimate goal is to regulate and restrict immunosuppression to the transplanted organ. In summary, this proposal explores applications of gene transfer techniques which aim to create a protected environment allowing acceptance of allogeneic cells, while maintaining normal systemic immunity.