Graft microvascular disease in solid organ transplantation

Abstract

Alloimmune inflammation damages the microvasculature of solid organ transplants during acute rejection. Although immunosuppressive drugs diminish the inflammatory response, they do not directly promote vascular repair. Repetitive microvascular injury with insufficient regeneration results in prolonged tissue hypoxia and fibrotic remodeling. While clinical studies show that a loss of the microvascular circulation precedes and may act as an initiating factor for the development of chronic rejection, preclinical studies demonstrate that improved microvascular perfusion during acute rejection delays and attenuates tissue fibrosis. Therefore, preservation of a functional microvasculature may represent an effective therapeutic strategy for preventing chronic rejection. Here, we review recent advances in our understanding of the role of the microvasculature in the long-term survival of transplanted solid organs. We also highlight microvessel-centered therapeutic strategies for prolonging the survival of solid organ transplants.

Fig. 1

Model summarizing how antibody and complement components induce endothelial accommodation and activation. Following antibody binding to MHC molecules or binding of antibody-activated complement components, such as C3a, C5a, and sublytic concentrations of C5b-9, endothelial cells express anti-apoptotic proteins such as Bcl-2, Bcl-XL, and HO-1; complement regulatory factors such as CD46, CD55, and CD59; adhesion molecules such as ICAM-1, VCAM-1, ELAM-1, E-selectin, and P-selectin; and chemotactic molecules such as CCL-20, CCL-5, IL-6, IL-1α, IL-8, and MCP-1. EC expression of these molecules is associated with endothelial accommodation or activation. Abbreviations: Bcl B-cell lymphoma, HO heme oxygenase, CD cluster of differentiation, ICAM intercellular adhesion molecule, VCAM vascular cell-adhesion molecule, ELAM endothelial cell-leukocyte adhesion molecule, E-selectin endothelial cell-selectin, P-selectin platelet-selectin, CCL CC-chemokine ligand, IL interleukin, MCP monocyte chemotactic protein

Fig. 2

Microvascular injury and the development of fibrosis. Normal microvasculature of the solid organ transplant can be damaged by immune cells such as CTLs, NK cells, macrophages, and neutrophils; antibody, complement, oxidative stress, and immunosuppressive drugs also induce vascular injury. Damaged microvasculature can be repaired and reversed to normal through local production of angiogenic factors, proliferation of resident vascular progenitor cells, as well as recruitment of recipient-derived proangiogenic cells. Insufficient microvascular repair leads to its remodeling. Both injured and remodeled microvasculature are functionally abnormal and results in tissue hypoxia followed by tissue fibroproliferation. In addition, vascular remodeling enhances both the endothelial cell to mesenchymal and pericyte to mesenchymal transition, both of which promotes fibrosis. Abbreviations: EC endothelial cell, PC pericytes, CTL cytotoxic T lymphocyte, NK natural killer