The Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice

Abstract

Antibody-mediated rejection (AMR) of solid organ transplants is characterized by the activation and injury of the allograft endothelium. Histological and transcriptomic studies have associated microvascular inflammation and endothelial lesions with the severity of rejection and poor graft outcomes. The allograft endothelium forms the physical barrier between the donor organ and the recipient; this position directly exposes the endothelium to alloimmune responses. However, endothelial cells are not just victims and can actively participate in the pathogenesis of rejection. In healthy tissues, the endothelium plays a major role in vascular and immune homeostasis. Organ transplantation, however, subjects the endothelium to an environment of inflammation, alloreactive lymphocytes, donor-specific antibodies, and potentially complement activation. As a result, endothelial cells become activated and have modified interactions with the cellular effectors of allograft damage: lymphocytes, natural killer, and myeloid cells. Activated endothelial cells participate in leukocyte adhesion and recruitment, lymphocyte activation and differentiation, as well as the secretion of cytokines and chemokines. Ultimately, highly activated endothelial cells promote pro-inflammatory alloresponses and become accomplices to AMR.

Keywords: antibody-mediated rejection; donor-specific antibodies; endothelial cells; inflammation; transplantation immunology.

Figure 1

Activated endothelial cells modulate allogenic T lymphocyte activity. Allogenic endothelial cells expressing HLA class II molecules are capable of inducing the secretion of IL-2 and alloproliferation by CD4+ memory lymphocytes. The T helper cell production of IL-2 facilitates the differentiation of memory CD8+ T cells into cytotoxic lymphocytes (CTLs), which can mediate rejection by targeting donor HLA class I molecules. Meanwhile, alloproliferation in CD4+ lymphocytes is associated with the selective expansion of pro-inflammatory Th17 (endothelial IL-6-dependent), anti-inflammatory Treg (endothelial ICAM-1 dependent) and pro-inflammatory Th1 subsets. Interestingly, donor-specific antibodies (DSAs) binding to HLA class II molecules alter endothelial cell immunogenicity. DSA binding can activate the Akt/PI3K-signaling pathway, consequently increasing endothelial IL-6 secretion and increasing the expansion of the pro-inflammatory Th17 subset. In addition, the amplification of the Treg population was decreased after DSA binding. Both the binding of DSA and the sub-lytic activation of the complement cascade can synergize to activate non-canonical NF-κB signaling in endothelial cells, ultimately resulting in an increased expansion of the Th1 subset and a greater secretion of IFNγ.

Figure 2

Endothelial cell activation and recruitment of natural killer (NK) cells and monocytes. (A) Donor-specific antibodies (DSAs) binding to endothelial cells may lead to the ligation of Fc receptors on NK cells and contribute to antibody-dependent cell-mediated cytotoxicity (ADCC) directed against the allograft or to the release of pro-inflammatory cytokines, such as interferon gamma (IFNγ). IFNγ is a key factor in the quantitative expression of HLA class II molecules. Changes in IFNγ could conceivably increase the targets for DSA and thus increase antibody-mediated damage. (B) During antibody-mediated rejection, Dll4 is upregulated on endothelial cells and is capable of modulating the differentiation of monocytes into macrophages displaying a pro-inflammatory M1 phenotype. (C) DSA binding to endothelial HLA class I molecules initiates intracellular signaling, such as the activation of ERK1/2, S6 kinase, S6 ribosomal protein, and mTOR. This signal transduction leads to the exocytosis of Weibel–Palade bodies and increases cell surface P-selection, which can augment monocyte recruitment and adhesion to the endothelial layer. Classical complement activation, resulting from DSA binding, is capable of synergizing with DSA signaling to further upregulate endothelial cell surface P-selectin and increase monocyte recruitment.