title: Transcutaneous gene gun delivery of hNC16A Induces BPAG2-specific tolerance.
abstract: Immune recognition and rejection of tissues expressing transfected genes is a major complication of gene replacement therapy for inherited genetic disorders. Owing to the high immunogenicity of human bullous pemphigoid antigen 2 (hBPAG2), the induction and maintenance of tolerance to this neo-antigen is essential to deliver the gene product to patients with epidermolysis bullosa junctionalis. In a skin grafting mouse model, we used gene gun transfection with a construct encoding hNC16A, the immunodominant domain of hBPAG2, to induce antigen-specific immune tolerance. Eighty percent of wild-type mice transfected with hNC16A showed long-term survival of skin grafts expressing hBPAG2. Tolerance was stable and transferable by T cells but not by B cells of tolerant mice to naive hosts. A dense Foxp3(+) regulatory T-cell (T(reg)) infiltrate was noticed in grafts of tolerant mice and depletion of these cells resulted in a loss of tolerance. Taken together, we show that long-lasting hBPAG2-specific tolerance was induced with gene gun delivery of hNC16A through a T(reg)-dependent mechanism. This is of relevance to patients undergoing gene therapy and has broader implications for the treatment of antigen-specific autoimmune diseases.
authors.affiliation: Division of Molecular Dermatology and EB House Austria, Department of Dermatology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Ettinger
authors.forename: Doris
authors.initials: D
authors.lastname: Peckl-Schmid
authors.forename: Christina
authors.initials: C
authors.lastname: Gruber
authors.forename: Martin
authors.initials: M
authors.lastname: Laimer
authors.forename: Josef
authors.initials: J
authors.lastname: Thalhamer
authors.forename: Helmut
authors.initials: H
authors.lastname: Hintner
authors.forename: Iris K
authors.initials: IK
authors.lastname: Gratz
authors.forename: Johann W
authors.initials: JW
authors.lastname: Bauer
mesh_terms: D000279:Administration, Cutaneous; D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D001485:Basement Membrane / Q000276:immunology; D003131:Combined Modality Therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D024041:Non-Fibrillar Collagens / Q000235:genetics* / Q000276:immunology; D010391:Pemphigoid, Bullous / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection / Q000379:methods; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII