RECIPIENT MESENCHYMAL CELLS INFILTRATE AND REMODEL MEDIAL AND ADVENTITIAL TISSUE IN THE RAT FEMORAL ARTERY ALLOGRAFT MODEL OF CHRONIC VASCULAR REJECTION

Abstract

139 Despite improvements in immunosuppressive regimens, the vascular narrowing produced by graft vascular disease continues to limit the long-term viability of several transplanted organs. The arterial intimal thickening is often explained by a four step process: (1) allo-immune/ischemic injury leads to integraft production of cytokines and growth factors, (2) initiation of smooth muscle cell (SMC) proliferation, (3) SMC migration to the intima, and(4) deposition of extracellular matrix. While steps 1,2, and 4 have been demonstrated by others, we explored the source of smooth muscle cells that migrated into the intima. Our results demonstrate for the first time that the SMC in the proliferating intima are not from the graft but are of recipient origin. We further demonstrate that a dramatic remodeling of donor medial and adventitial tissue with recipient mesenchymal cells occurs.METHODS: Femoral arteries from Brown Norway (BN, RT1.An) were transplanted orthotopically into Lewis (LEW, RT1.Al) recipients for 40 days. Femoral isografts were also performed. Arterial sections were stained with fluorescently-labeled antibodies (mAB) specific for BN or LEW MHC class I antigens. Percent intimal area was evaluated by morphometric analysis. Cellular infiltrates and cytokines were evaluated by immunohistochemistry and in situ hybridization.RESULTS: Mean percent intimal area for allografts removed after 40 days was 49% (n=18) compared to 5% in 40 day LEW to LEW isografts (n=5). The intima, media, and adventitia contained infiltrates of T cells (CD4+ & CD8+) and macrophages, as well as increased mRNA expression of PDGFα, bFGF, TGFβ, IL-1, IL-2, and IFN-γ compared to isograft controls. Approximately 50% of allograft intimal cells contained smooth muscle action. Each anti-MHC I antibody specifically stained smooth muscle, fibroblast, mononuclear, and endothelial cells of 40 day isografts from only the corresponding rat strain. In 40 day allografts, all mesenchymal and immune cells in the intima were of recipient (LEW) origin. Furthermore, the mesenchymal cells of the media, and to a lesser extent the adventitia, were also of recipient origin indicating that a dramatic remodeling of arterial tissue had occurred without a visible disruption of tissue organization.CONCLUSIONS: (1) We report the novel finding that intimal thickening in rat femoral allografts results not from a proliferation of SMC of donor origin in the graft, as has been previously assumed, but from infiltrating mesenchymal cells of recipient origin. (2) A dramatic remodeling of medial and adventitial cells by recipient mesenchymal cells occurred in association with intimal thickening.