Expanding role of antibodies in kidney transplantation

Abstract

The role of antibodies in kidney transplant (KT) has evolved significantly over the past few decades. This role of antibodies in KT is multifaceted, encompassing both the challenges they pose in terms of antibody-mediated rejection (AMR) and the opportunities for improving transplant outcomes through better detection, prevention, and treatment strategies. As our understanding of the immunological mechanisms continues to evolve, so too will the approaches to managing and harnessing the power of antibodies in KT, ultimately leading to improved patient and graft survival. This narrative review explores the multifaceted roles of antibodies in KT, including their involvement in rejection mechanisms, advancements in desensitization protocols, AMR treatments, and their potential role in monitoring and improving graft survival.

Keywords: Antibodies; Humoral theory; Kidney transplantation; Rejection.

Figure 1

Mechanisms of antibody-mediated graft injury. The chief target of antibodies consists of vascular endothelial cells. A: Antibodies recognize class I and II human leucocyte antigens (HLA) as foreign and bind to them; B: This antibody binding to donor HLA antigens leads to complement-fixing and generation of anaphylatoxins and assembly of the membrane attack complex; C: Antibodies can also damage the graft tissue by antibody-dependent cellular cytotoxicity by engaging inflammatory cells. HLA: Human leucocyte antigen. This figure was created by BioRender.com (Supplementary material).

Figure 2

Mechanisms of action of non-human leucocyte antigen antibodies. A: The targets of these antibodies are non-human leucocyte antigens (HLA) molecules expressed on endothelial cells. Non-HLA antibodies recognize various antigens such as angiotensin type 1 receptor and endothelin A receptor on endothelial cells and bind to them; B: This antibody binding to donor non-HLA antigens leads to complement-fixation and generation of anaphylatoxins (C3a and C5a) and recruitment of inflammatory cells. These antibodies can also activate the endothelial cells resulting in increased expression of HLA, non-HLA, and adhesion molecules such as intercellular adhesion molecule and vascular cell adhesion molecule; C: This results in damage to the endothelial cells, initiation of thrombogenesis, and induction of apoptosis of these cells, ultimately resulting in microvascular injury, thrombosis, and inflammation. HLA: Human leucocyte antigen; ICAM: Intercellular adhesion molecule; VCAM: Vascular cell adhesion molecule. This figure was created by BioRender.com (Supplementary material).

Figure 3

Pathology of acute antibody-mediated graft injury. The principal target of antibodies is the microcirculation and larger blood vessels. A: Severe glomerulitis. Many of the glomerular capillary lumens are obliterated by inflammatory cell infiltration (HE, × 400); B: A glomerulus showing fibrin thrombi obliterating some of the capillary lumens (arrow) (HE, × 200); C: A focus of moderate peritubular capillaritis (ptc2) (arrow) (HE, × 400); D: Diffuse C4d positivity (C4d) (C4d3) in peritubular capillaries (FITC, IF for C4d, × 200).

Figure 4

Pathology of acute and chronic antibody-mediated graft injury. The principal target of antibodies is the microcirculation and larger blood vessels. A: Severe interstitial fibrosis and tubular atrophy. This lesion is entirely non-specific and may result from a variety of immune and non-immune causes [Periodic acid-Schiff (PAS) stain, × 200]; B: A glomerulus showing double contouring of capillary walls and an occasional inflammatory cell infiltration obliterating the capillary lumen (arrow) (PAS, × 400); C: A small artery exhibiting fibrinoid necrosis of the wall (v3). This lesion is strongly suggestive of active antibody-mediated rejection (AMR) (HE, × 400); D: Moderate fibrointimal thickening of an interlobular size artery. This lesion may be seen in chronic AMR as well as chronic T cell-mediated rejection (Trichrome stain, × 400).