Subclass of Donor-specific Antibody as a Risk Factor of Antibody Mediated Rejection in Renal Transplantation

Overview

Antibody-mediated rejection is now recognized as the first cause of long-term kidney transplant loss. This type of rejection is mediated by the presence of graft-specific antibodies, usually directed against HLA (Human Leukocyte Antigens), called DSA (Donor Specific Antibody). De novo DSA (ie, post-transplantation) is detected in approximately 20% of transplant recipients in the first five years, and is a major risk factor for antibody mediated rejection and graft loss. All anti-HLA antibodies therefore do not have the same pathogenicity. Some teams have shown that the detection of IgG3 anti-HLA by cytometry is associated with a higher risk of humoral rejection but these results have not been confirmed by others. One of the limitations of the cytometry by Luminex technique is that it only informs the detection of each subclass but does not allow analysis of the distribution of the different subclasses of a DSA. A method has been developed for the relative detection and quantification of different subclasses of the DSA using the mass spectrometry technique and will be tested during this study. This new quantification method therefore opens up the prospect of studying whether, not only the presence but especially the distribution of IgG subclasses, in particular IgG3, could constitute a reliable and robust marker of humoral rejection.

Antibody-mediated rejection is now recognized as the first cause of long-term kidney transplant loss. This type of rejection is mediated by the presence of graft-specific antibodies, usually directed against HLA (Human Leukocyte Antigens), called DSA (Donor Specific Antibody). It results from the interaction between DSA and HLA present on the surface of graft endothelial cells, complement activation, endothelial cell activation and recruitment of inflammatory cells within the renal microcirculation leading to a graft dysfunction. De novo DSA (ie, post-transplantation) is detected in approximately 20% of transplant recipients in the first five years, and is a major risk factor for antibody mediated rejection and graft loss. However, the presence of a DSA is not always associated with humoral rejection. All anti-HLA antibodies therefore do not have the same pathogenicity. The antibody titre (assessed by the fluorescence average (MFI) on Luminex beads) is involved in the risk of rejection but is far from explaining the disparities in clinical evolution. DSA are mainly IgG of different subclasses whose distribution could have a major impact on their pathogenicity. Indeed, complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) functions differ according to IgG subclass. IgG3 is the subclass that has the greatest potential for complement activation followed by IgG1. IgG3 and IgG1 are also the two subclasses with the best affinities for the FcγRIIIa activating receptor for ADCC mediated by Natural Killer (NK) cells. Some teams have shown that the detection of IgG3 anti-HLA by cytometry is associated with a higher risk of humoral rejection but these results have not been confirmed by others. One of the limitations of the cytometry by Luminex technique is that it only informs the detection of each subclass but does not allow analysis of the distribution of the different subclasses of a DSA. A method has been developed for the relative detection and quantification of different subclasses of the DSA using the mass spectrometry technique and will be tested during this study. This new quantification method therefore opens up the prospect of studying whether, not only the presence but especially the distribution of IgG subclasses, in particular IgG3, could constitute a reliable and robust marker of humoral rejection.