This Review Is Part of a Thematic Series on Transplant Vasculopathy, Which Includes the following Articles: Allograft Vasculopathy versus Atherosclerosis Antibody and Complement in Transplant Vasculopathy Interferon-␥ Axis in Graft Arteriosclerosis Vascular Remodeling in Transplant Vasculopathy Chem

—As therapeutic strategies to prevent acute rejection progressively improve, transplant vasculopathy (TV) constitutes the single most important limitation for long-term functioning of solid organ allografts. In TV, allograft arteries characteristically develop severe, diffuse intimal hyperplastic lesions that eventually compromise luminal flow and cause ischemic graft failure. Traditional immunosuppressive strategies that check acute allograft rejection do not prevent TV; indeed 50% of transplant recipients will have significant disease within five years of organ transplantation, and 90% will have significant TV a decade after their surgery. TV can involve the entire length of the transplanted arterial bed, including penetrating intraorgan arterioles. Indeed, the luminal narrowing of such penetrating vessels may be the most functionally significant because arterioles represent the major contributors to tissue vascular resistance. Because of the diffuseness of TV involvement in the allograft vascular bed, the only currently definitive therapy requires re-transplantation. Nevertheless, as we better understand the pathogenesis and critical mediators of these lesions, pharmacological advances can be anticipated. Other articles in this thematic review series focus on the specifics of the inciting injury, the cytokines and chemokines that drive TV development, and the nature of the recruited cells in TV lesions, as well as the pathogenic similarities between TV and other vascular lesions such as atherosclerosis. This review focuses on the mechanisms of vascular wall remodeling in TV, including the intimal accumulation of smooth muscle–like cells and associated extracellular matrix, medial smooth muscle cell degeneration, and adventitial fibrosis. A brief overview highlights the aneurysmal changes that can accrue when vessel wall inflammation has a cytokine profile distinct from the typical proinflammatory interferon-␥– dominated milieu. W e originally hypothesized, more than a decade ago, that transplant vasculopathy (TV) represented an ineffective delayed-type-hypersensitivity response directed against donor endothelial cells (ECs) and medial smooth muscle cells (SMCs). 1,2 Although the alloresponse does not effectively eliminate the donor vascular wall cells, injured and dysfunc-tional ECs and SMCs will nevertheless participate in the recruitment and activation of medial SMCs to progressively occlude the vascular lumen. Although a number of the details have since been refined, subsequent work has largely borne out the original hypothesis. Donor arterial ECs and SMCs are preserved in long-term allografts. 3,4 Whether these cells persist because hosts develop an attenuated allograft response 5,6 or because the grafts otherwise accommodate to humoral mediators, ECs and SMCs potentially can act as ongoing targets of an allore-sponse. Interestingly, even in experimental situations …