Donor-Specific Antibodies in Kidney Transplant Recipients

Abstract

Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.

Keywords: Biomarkers; C1q-binding DSA; Complement System Proteins; Humans; IgG subclasses; Immunoglobulin G; Phenotype; Receptors, Fc; Tissue Donors; antibody-mediated rejection; donor specific antibody; kidney transplantation.

Figure 1.

The three proposed pathogeneses of donor-specific antibodies (DSAs) in antibody-mediated rejection. Donor antigen-presenting cells include macrophages, dendritic cells, and B cells. Complement binding DSAs target the class 1 HLA on endothelial cells, activate the classic complement cascade, and deliver complement-dependent cytotoxicity in acute antibody-mediated rejection. Complement nonbinding DSAs recruit innate immune cells (NK cells, macrophages, and neutrophils) through Fc receptors and lead to antibody-dependent cellular toxicity. In addition, complement nonbinding DSAs have direct stimulation and pleotrophic effects that cause tissue injury, cellular recruitment, and endothelial proliferation. The latter two mechanisms play an important role in acute antibody-mediated rejection with negative C4d deposit in peritubular capillaries as well as chronic antibody-mediated rejection, transplant glomerulopathy, and vasculopathy (,,,–24). APC, antigen-presenting cells; NK, natural killer cells.