Failing Heart Transplants and Rejection—A Cellular Perspective

Figures

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  Figure 1. Ischemia and reperfusion induce many cellular changes. During ischemia, all cell types are hypoxic and shift to anaerobic metabolism accompanied with a decrease in pH. As a consequence, the level of Ca2+ increases. During reperfusion, release of ROS and DAMPs will lead to immune activation with cytokine release, expression of adhesion molecules in endothelial cells and to recruitment of immune cells, as well as platelet and complement activation. The metabolic switch to aerobic accompanied by high intracellular Ca2+ may cause hypercontracture of the cardiac muscle. ROS = reactive oxygen species, DAMPs = damage associated molecular patterns.

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  Figure 2. (A). Different T cell allorecognition pathways. In direct allorecognition, donor derived APCs present donor allopeptides on a donor MHC to the recipient’s T-cells, which leads to donor allorecognition. In indirect allorecognition, recipient derived APCs present a donor allopeptide on MHC molecule to the recipient’s T-cell. In semi-direct allorecognition, recipient APC catches a donor MHC molecule, which is transported to the cell surface and presented to T-cells. (B). In cellular rejection, alloreactive cytotoxic CD8+ T cells have been activated in secondary lymphoid organs by activated antigen presenting cells either via direct or indirect allorecognition. Once they encounter cells presenting target antigens on HLA I molecule, the target cells, which are typically ECs, will be killed. (C). AMR is characterized by injury of the allograft endothelium and presents as microvascular inflammation. First, donor derived antigen is presented by APCs to CD4+ T-cells in the secondary lymphoid organ. Hence, CD4+ T cells activate B cells and the formation of plasma cells, producing donor specific antibodies (DSAs). Upon DSA (IgG) binding to target cells, which are typically ECs, the…

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  Figure 3. (A). Cardiac allograft vasculopathy presents as diffuse intimal thickening of coronary arteries and microvasculature, which is also accompanied by infiltration of immune cells. (B). Repetitive EC injuries by ischemia reperfusion injury and rejection episodes initiate the development of CAV. Upon these injuries, ECs upregulate adhesion molecules and recruit leukocytes. Consequent upregulation of cytokines and growth factors will lead to migration and/or proliferation of intimal SMCs as well as endothelial mesenchymal transition, increased resistance to apoptosis, increased ECM production and fibrosis. I/R injury = ischemia reperfusion injury, DAMPs = damage associated molecular patterns, ROS = reactive oxygen species.