Dendritic cells expressing soluble CTLA4Ig prolong antigen-specific skin graft survival.

Abstract

Dendritic cells (DCs) and CTLA4Ig are important in regulating T-cell responses and therefore represent potential therapeutic tools in transplantation. In this study, CTLA4Ig was expressed in a C57BL/6 murine DC line (JAWS II) by lentiviral transduction and these cells were used to examine T-cell immunomodulatory effects in vitro and in vivo. A lower stimulation index to C57BL/6 was observed with splenocytes from BALB/c mice primed with JAWS II-CTLA4Ig compared with control JAWS II-green fluorescent protein (JAWS II-GFP). Mice primed with JAWS II-CTLA4Ig cells had significantly prolonged antigen-specific C57BL/6 skin graft survival compared with either JAWS II-GFP-primed or naïve mice (median 13, 11 and 11 days, respectively, P=0.0001). Furthermore, JAWS II-CTLA4Ig-primed mice that had been previously transplanted with skin grafts were re-transplanted with skin grafts 6 months later without immune manipulation. These mice demonstrated specific prolongation of second-set rejection responses, indicating systemic immune modulation induced by genetically modified DC. The mechanism was not due to expression of indoleamine 2,3-dioxygenase or induction of circulating regulatory T cells as assessed by flow cytometry of the peripheral blood lymphocytes. This potent effect demonstrated with skin grafts and second-set responses highlights the potential use of this strategy for transplantation more generally.