Transgenic Expression of Cytotoxic T-Lymphocyte-Associated Antigen 4-Immunoglobulin Prolongs Xenogeneic Skin Graft Survival Without Extensive Immunosuppression in Rat Burn Wounds

Abstract

We sought to establish a transgenic animal line skin-specifically overexpressing cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) as a reproducible source of xenogeneic skin grafts with extended survival for wound coverage. We tested this strategy in mice based on a previously established transgenic mouse line that stably and skin-specifically expresses CTLA4Ig for lifetimes and generations. CTLA4Ig expression was examined by immunohistochemical assay, and its bio-activity was tested by mixed lymphocyte reaction. The survival of transgenic mouse skin grafted onto rat burn wounds was observed. The impact of transgenic skin grafting on recipient immunity was evaluated by inspecting the survival of the wild-type skin grafted along with transgenic skin onto a separate wound on the same rat. The circulatory CTLA4Ig protein in recipient was detected by sandwich enzyme-linked immunosorbent assay, and its impact on recipient lymphocyte response against donor antigen was tested by mixed lymphocyte reaction. The transgenic CTLA4Ig protein suppressed lymphocyte proliferation in vitro, and the transgenic skin graft survival was remarkably prolonged compared with the wild-type skin derived from the same mouse strain. The survival of the wild-type skin grafted along with transgenic skin exhibited no significant difference from that grafted alone. Circulatory CTLA4Ig protein was detected in recipients, however, no significantly reduced recipient lymphocyte response against donor antigen was observed. transgenic expression of CTLA4Ig may be a potential and safe method to prolong xenogenic skin graft survival in burn wounds, and transgenic animal lines can be established as a reproducible source of skin grafts with extended survival for wound coverage.