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.

Therapeutic potential of semi-mature dendritic cells for tolerance induction

“…Although not further investigated, it is likely that ssmDCs have been the vehicle to induce myelin-specific Tregs in the skin-draining lymph nodes. Surprisingly, even approaches using gene gun delivery of antigens, that has been developed for immunogenic vaccines, may be used to induce stable tolerance by induction of Foxp3+ Tregs and this may occur through ssmDCs (Ettinger et al, 2012). …”

Evidence for pathogenicity of autoreactive T cells in autoimmune bullous diseases shown by animal disease models

“…Ettinger et al . recently reported that transcutaneous gene gun delivery of hCOL17‐NC16A induced immune tolerance towards hCOL17, a neo‐antigen for wild‐type mice, in a Treg‐dependent manner. Antigen‐specific immunosuppressive effects by DNA vaccination have also been shown in ongoing autoimmune disease models such as experimental autoimmune encephalomyelitis and type 1 diabetes .…”

A gene network bioinformatics analysis for pemphigoid autoimmune blistering diseases

“…However, in relation to the antigens involved, it is possible to differentiate bullous, mucous membrane, gestationis and anti-p200 pemphigoid diseases as well as linear IgA dermatosis, epidermolysis bullosa acquisita and lichen planus pemphigoides [9]. In order to discover the molecular basis of new diseases, the genomic approach can disclose multiple protein and gene interactions that could heavily influence patient susceptibility; moreover, the application of gene replacement therapy for inherited genetic disorders seems to be a promising strategy [23,24].…”