Abstract
Allograft vasculopathy (AV) remains one of the major challenges to the long-term functioning of solid organ transplants. Although its exact pathogenesis remains unclear, AV is characterized by both fibromuscular proliferation and infiltration of CD4+ memory T cells. We here tested whether two experimental immunosuppressants targeting K+ channels might be useful for preventing AV. PAP-1 inhibits the voltage-gated Kv1.3 channel, which is overexpressed on CCR7− memory T cells and we therefore hypothesize that it should suppress the memory T cell component of AV. Based on its previous efficacy in restenosis and kidney fibrosis we expected that the KCa3.1 blocker TRAM-34 would primarily affect smooth muscle and fibroblast proliferation and thus reduce intimal hyperplasia. Using immunohistochemistry we demonstrated the presence of Kv1.3 on infiltrating T cells and of KCa3.1 on lymphocytes as well as on proliferating neointimal smooth muscle cells in human vasculopathy samples and in a rat aorta transplant model developing chronic AV. Treatment of PVG rats receiving orthotopically transplanted aortas from ACI rats with TRAM-34 dose-dependently reduced aortic luminal occlusion, intimal hyperplasia, mononuclear cell infiltration and collagen deposition 120 days after transplantation. The Kv1.3 blocker PAP-1 in contrast did not reduce intima hyperplasia despite drastically reducing plasma IFN-γ levels and inhibiting lymphocyte infiltration. Our findings suggest that KCa3.1 channels play an important role in the pathogenesis of chronic AV and constitute an attractive target for the prevention of arteriopathy.
Highlights
Allograft vasculopathy (AV), a concentric thickening of the arteries in transplanted hearts or kidneys leading to luminal obliteration and ischemic graft failure, remains one of the major challenges to the long term functioning of solid organ transplants [1]
In order to determine if both channels are present and potentially involved in the pathogenesis of vasculopathy, we stained sections from a coronary artery from a patient with atherosclerotic changes and from a mammary artery coronary artery bypass graft (CABG), both exhibiting pronounced intimal hyperplasia, for Kv1.3 and KCa3.1 (Figure 1A-D)
Many lesions contained inflammatory infiltrates consisting of CD3+ T cells and CD68+ macrophages and/or demonstrated features of atherosclerosis, Figure 6. (A) PAP-1, high dose sirolimus and the combination of low dose sirolimus and low dose TRAM-34 strongly reduce circulating IFN-c levels
Summary
Allograft vasculopathy (AV), a concentric thickening of the arteries in transplanted hearts or kidneys leading to luminal obliteration and ischemic graft failure, remains one of the major challenges to the long term functioning of solid organ transplants [1]. AV, which is sometimes called transplant arteriosclerosis resembles atherosclerosis in many respects In both diseases the endothelium is dysfunctional and damaged; fostering inflammation, increased intimal thickening, and eventually the development of medial smooth muscle cell degeneration, and adventitial fibrosis [2]. Histopathology in both conditions demonstrates the involvement of T cells, monocytes/macrophages, and proliferating vascular smooth muscle cells as well as fibrotic changes. The fact that AV can even occur following ischemic injury in isografts [6] or in T-cell depleted hosts after a transient episode of rejection [7], suggests that once initiated, dedifferentiated smooth muscle cells of both donor and recipient origin as well as activated and injured endothelial cells participate in the ongoing vasculopathy leading to luminal obliteration. Most clinically used immunosuppressive regiments, while quite effective at preventing acute allograft rejection, fail to prevent AV and 50% of grafts will show significant arteriopathy within 5 years after transplantation, while 90% will be affected within 10 years [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
