IMMUNE

$272,049P01FY2006HLNIH

Wistar Institute, Philadelphia PA

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Abstract

The central hypothesis of this proposal is that controlling the function of CD4+25+ reguhatory T cells (Treg) in[unreadable] vivo will abrogate cellular and humoral immune responses to human coagulation factor IX (hF.IX) antigen,[unreadable] which is administered by adeno-associated viral (rAAV) gene transfer. Because markers of Treg cells have[unreadable] only recently become available, it is now possible to enhance the number of activated Treg cells in vivo.[unreadable] The experiments proposed in this application are designed to examine the contributions and limitations of[unreadable] GITR and GITR-Ligand based on/off switches of Treg cell suppression of cell-mediated and humoral immune responses elicited by rAAV-hF.IX gene transfer. Secondly, adoptive transfer based cell therapy with Treg cells will be applied to control the rAAV-hF.IX induced cell-mediated responses. Third a strategy that targets activated cytopathic reactive T cells and spares immunoregulatory networks will be adapted from the transplantation field.[unreadable] The experiments proposed in this application are grouped in the following specific aims:[unreadable] Specific Aim #1: To test the hypothesis that administering a soluble GITR-Ligand-Fc fusion protein [Fc-[unreadable] GITR-L] inactivates Treg cell functions and thus enhances humoral and cellular immune responses to rAAV-hF.[unreadable] IX.[unreadable] Specific Aim #2: To test the hypothesis that treatment with a monoclonal antibody directed at mouse GITR-L enhances Treg cell suppression and immune tolerance to hF.IX antigens and AAV capsid antigen.[unreadable] Specific Aim #3: To test the hypothesis that suppression and/or deletion of potentially pathogenic T cells facilitates Treg mediated immunologic tolerance towards hF.IX..[unreadable] Together these experiments should clarify the role of Treg cell controlled pathways in rAAV hF.IX gene[unreadable] therapy. The results of these studies should suggest therapeutic strategies that can immediately be applied[unreadable] to hemophilia patients.

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