Cardiac allograft vasculopathy: a donor or recipient induced pathology?

Abstract

Cardiac allograft vasculopathy (CAV) is one of the main causes of late-stage heart failure after heart transplantation. CAV is characterized by concentric luminal narrowing of the coronary arteries, but the exact pathogenesis of CAV is still not unraveled. Many researchers show evidence of an allogeneic immune response of the recipient, whereas others show contrasting results in which donor-derived cells induce an immune response against the graft. In addition, fibrosis of the neo-intima can be induced by recipient-derived circulating cells or donor-derived cells. In this review, both donor and recipient sides of the story are described to obtain better insight in the pathogenesis of CAV. Dual outcomes were found regarding the contribution of donor and recipient cells in the initiation of the immune response and the development of fibrosis during CAV. Future research could focus more on the potential synergistic interaction of donor and recipient cells leading to CAV.

Fig. 1

Microscopic pictures of the three histopathological phenotypes of CAV in the coronary artery of heart transplantation recipients. a H-CAV 1 lesion, which shows infiltration of lymphocytes in the neo-intima layer; H-CAV 2 lesion, showing infiltration of lymphocytes together with infiltration of smooth muscle cells and formation of connective tissue; H-CAV 3 lesion, which shows a large fibrotic intimal lesion without inflammatory infiltrate (αSMA staining, magnification ×100, line indicates 100 μm). b Microscopic pictures of occluded coronary arteries by a thrombus or fibrotic tissue, respectively (HE staining, magnification ×20, line indicates 1 mm)

Fig. 2

Pathways in recipient-derived immune response. Primary event is the recognition of allo-antigens by T-lymphocytes via one of the indicated pathways. The direct pathway is activated by the recognition of MHC complexes with a foreign HLA-antigen (red) presented by donor APCs (red). The indirect pathway is activated when T-lymphocytes recognize processed allo-antigens presented by recipient APCs (green). The semi-direct pathway is activated when T-lymphocytes recognize allo-antigens presented on donor MHC on recipient APCs. In addition, non-HLA antigens might be involved, which are bound by “auto-antibodies”. This will lead to complement activation and T-lymphocyte activation. Activation of B-cells can be initiated by donor DCs and donor T-lymphocytes. All of the indicated pathways lead to activation of T-lymphocytes, which start to secrete pro-inflammatory cytokines such as IFN-γ. The secretion of IFN-γ recruits more immune cells, such as NK-cells and macrophages, and acts on SMCs. The proliferation of SMCs will ultimately result in proliferation of the intima and occlusion of the artery, which are the characteristics of CAV

Fig. 3

Role of recipient and donor-derived cells in concentric narrowing and fibrosis of the coronary artery. a Recipient-derived circulating cells, such as EPCs and ECPCs, contribute to concentric narrowing and fibrosis of the coronary arteries. Increased accumulation of circulating cells bound to the vessel wall induces differentiation of these cells toward fibroblasts, SMCs, and endothelial cells, which enhances concentric narrowing of the coronary arteries. b. Donor-derived cells, such as SMCs, are migrating from atherosclerotic lesions or the media layer toward the neo-intima. Accumulation of donor-derived SMCs and production of ECM will lead to the expansion of the neo-intima resulting in narrowing and fibrosis of the coronary artery