Enigma of graft vascular disease: Are we still interested in getting the answers?
Authors: Subbotin Vladimir Michael 
Published: June 2021

Chronic rejection, chiefly graft vascular disease (GVD), or neointimal formation, is the main obstacle in organ transplantation. The traditional pathogenesis hypothesis assumes that due to the introduction of alloantigens, the activated immune system affects graft arteries, causing arterial neointimal formation or GVD. However, all potential causative components of the immune system have been thoroughly investigated without clinical results. The introduction of powerful immunosuppressants—immunophilins, which are highly effective in controlling acute rejection—has little or no effect on rates of GVD. Additionally, autologous vascular graft transplantations are plagued by the same neointimal formations, altogether bringing doubts that the immunologic hypothesis is sufficient to explain the pathogenesis. Over the last decade, the immunologic model of GVD was complemented by a variety of non‐immunological causes, varying in nature and magnitude. Therefore, all hypotheses on GVD pathogenesis assumed that: 1) neointimal formation is a novel pathological phenomenon caused by new mechanisms; and 2) causative factors of GVD are exogenous with respect to the affected arteries, whether they are of immunologic or non‐immunologic nature. However, these assumptions are not coherent with basic facts on human vascular biology. Intimal cell proliferation and normal neointimal formation, or diffuse intimal thickening (DIT), are inherent properties of human arteries. This morphogenesis occurs in all humans, and normal DIT is striking in its resemblance to GVD. In human post‐natal ontogenesis, the tunica intima of all arteries is initially formed as a single cell layer compartment (endothelium). During development, this arterial design has differentiated into two normal variants of the tunica intima phenotypes. The first phenotype resumes single cell layer intimal morphology, the characteristic of small and medium arteries. The second phenotype is produced by proliferation of a single layer endothelium into a multi‐layered cellular intimal compartment, i.e., DIT or normal neointima, which is characteristic of the epicardial coronary and main elastic arteries. Normally both phenotypes are controllable, remaining stable for a lifetime in the majority of the population, but both phenotypes can slip into uncontrolled neointimal proliferation due to a variety of non‐specific triggering signals. Considering that the mechanisms controlling phenotypic stability are still obscure, the study of these mechanisms, rather than non‐specific triggering signals, should inform research priorities. Therefore, the basic research on chronic rejection, GVD morphogenesis and mechanisms controlling tunica intima phenotypes is anticipated to have recently increased. In contrast, a PubMed search for the relevant keywords in the Title/Abstract section revealed that the number of these publications has either decreased or remained the same, while the number of organ/limb/tissue composite transplantation publications has increased significantly (Figure 1). This is a very dangerous trend. Conclusions: Two questions should inform the priorities of our research: 1) what controls the switch of the single cell layer intimal phenotype into normal neointima or DIT? and 2) what controls the stability of normal neointima, or DIT? We will be hard‐pressed to gain practical insights into chronic rejection and GVD pathogenesis without answering these questions.

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This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.