Local Expression of Indoleamine 2,3-Dioxygenase Protects Engraftment of Xenogeneic Skin Substitute

The expression of indoleamine 2,3-dioxygenase (IDO), which metabolizes tryptophan, an essential amino acid, into kynurenine, has been identified as having a key role in the prevention of the immune rejection of the semi-allogeneic fetus during pregnancy. We have previously demonstrated that IDO expressed in fibroblasts causes bystander CD4+ T cell damage as well as THP-1 cell damage by apoptosis. As T cells are primarily responsible for graft rejection, here, we asked the question of whether engraftment of IDO-expressing xenogeneic fibroblasts populated in a collagen matrix can be immuno-protected in an animal model. The results show a significant reduction in the number of infiltrated CD3+ T lymphocytes on days 14 and 28 post-transplantation in the wounds receiving IDO-expressing fibroblasts relative to controls. IDO-expressing human fibroblasts embedded in bovine collagen on wounds in a rat model accelerates wound healing by promoting neovascularization during the early stages and providing protection of the xenograft fibroblasts. Using a co-culture system, we further confirm that IDO can induce angiogenesis through the depletion of tryptophan. These findings suggest that IDO may have an application in promoting the engraftment of skin substitutes and other transplanted organs.