Controlling immune response to specific antigens

Abstract

One major problem with adenovirus gene therapy has been the T-cell mediated immune response elicited by inoculation of adenovirus, which leads to rapid clearance of the virus and loss of transgene expression. In the instant invention, the immune response to a virus is prevented by pre-treatment with adenovirus, adenoassociated virus or herpes virus infected antigen-presenting cell (APC) expressing Fas ligand with induced T-cell tolerance. Administration of AdCMVLacZ after tolerance resulted in prolonged expression of LacZ in tolerized animals compared to control treated animals. In control, but not tolerized animals, there was proliferation of CD3 + T-cell in the spleen in response to AdCMVLacZ treatment. Tolerance induction is also indicated by decreased production of interferon-γ and IL-2 by peripheral T-cells isolated from treated animals after stimulation with the adenovirus infected APCs. T-cell tolerance is specific for the virus as the T-cell responses to an irrelative virus, mouse cytomegalovirus (MCMV) remained unimpaired. The instant invention utilizes virus specific T-cell tolerance, which is induced by APCs that co-express Fas ligand and virus antigens. The instant invention involves novel vectors and methods to induce tolerance to a viral vector gene therapy and prolong expression of a transgene in a viral host.

1 . A method for promoting immunotolerance in a host to a gene therapy vector, comprising the step of: 
 transfecting a host cell with said vector, such that said vector expresses a transgene, an antigen and a Fas 2 ligand, wherein expression of said Fas 2 ligand induces apoptosis in a T-cell raised against said antigen in the host.    
     
     
         2 . The method of  claim 1  further comprising the step of: 
 exposing said host to a second vector following therapeutic gene expression, said second vector expressing said antigen and a second ligand wherein expression of said second ligand induces apoptosis in said T-cell.  
 
     
     
         3 . The method of  claim 2  wherein said second ligand induces apoptosis of said T-cell by the same mechanism as said Fas 2 ligand.  
     
     
         4 . The method of  claim 3  wherein said Fas 2 ligand interacts with a death domain region molecule DRX of said T-cell, wherein X is selected from the group consisting of 3, 4, and 5.  
     
     
         5 . The method of  claim 1  wherein transfecting said host cell occurs in vitro.  
     
     
         6 . The method of  claim 1  wherein transfecting said host cell occurs in vivo.  
     
     
         7 . The method of  claim 6  wherein transfecting said host cell occurs by an intra-nasal pathway.  
     
     
         8 . The method of  claim 6  wherein transfecting said host cell occurs by an intravenous pathway.  
     
     
         9 . The method of  claim 1  wherein said vector is selected from the group consisting of: a recombinant adenovirus, a recombinant adeno-associated virus, and a recombinant herpes virus.  
     
     
         10 . The method of  claim 1  wherein said vector is selected from the group consisting of: adenovirus, adeno-associated virus and herpes virus.  
     
     
         11 . The method of  claim 10  wherein said vector is replication defective.  
     
     
         12 . The method of  claim 10  wherein said vector encodes only nonpathogenic polypeptides.  
     
     
         13 . The method of  claim 1  wherein said antigen is a polypeptide encoded for by a vector associated gene.  
     
     
         14 . A method for creating an immune privileged site in a tissue of an organism, said method comprising the steps of: 
 providing a gene therapy vector encoding and expressing a Fas 2 ligand, a transgene and an antigen in the tissue of the organism; and    infecting cells of said tissue with said vector, whereby expression of the Fas 2 ligand in said tissue induces apoptosis of T-cells raised against said antigen to confer specific immunity to infected cells.    
     
     
         15 . The method of  claim 14  further comprising the step of: reinfecting said tissue with said vector so as to prolong expression of said therapeutic gene.  
     
     
         16 . The method of  claim 14  wherein said transgene is selected from the group consisting of CFTR, Factor 8, protease inhibitor and insulin.  
     
     
         17 . The method of  claim 14  wherein said vector is a recombinant adenovirus.  
     
     
         18 . The method of  claim 14  wherein said vector is selected from the group consisting of: adenovirus, adeno-associated virus and herpes virus.  
     
     
         19 . The method of  claim 18  wherein said vector is replication defective.  
     
     
         20 . The method of  claim 18  wherein said vector encodes only nonpathogenic polypeptides.  
     
     
         21 . A gene therapy viral vector comprising: 
 a transgene;    a viral vector gene that is expressed as an antigen on an infected host cell;    a Fas 2 ligand gene; and    a gene expression control means for directing product synthesis of said transgene and said Fas 2 ligand gene in a host.