Subclass analysis of donorHLA‐specific IgG in antibody‐incompatible renal transplantation reveals a significant association of IgG₄with rejection and graft failure

Abstract

SummaryDonor HLA‐specific antibodies (DSAs) can cause rejection and graft loss after renal transplantation, but their levels measured by the current assays are not fully predictive of outcomes. We investigated whether IgG subclasses of DSA were associated with early rejection and graft failure. DSA levels were determined pretreatment, at the day of peak pan‐IgG level and at 30 days post‐transplantation in eighty HLA antibody‐incompatible kidney transplant recipients using a modified microbead assay. Pretreatment IgG4 levels were predictive of acute antibody‐mediated rejection (P = 0.003) in the first 30 days post‐transplant. Pre‐treatment presence of IgG4 DSA (P = 0.008) and day 30 IgG3 DSA (P = 0.03) was associated with poor graft survival. Multivariate regression analysis showed that in addition to pan‐IgG levels, total IgG4 levels were an independent risk factor for early rejection when measured pretreatment, and the presence of pretreatment IgG4 DSA was also an independent risk factor for graft failure. Pretreatment IgG4 DSA levels correlated independently with higher risk of early rejection episodes and medium‐term death‐censored graft survival. Thus, pretreatment IgG4 DSA may be used as a biomarker to predict and risk stratify cases with higher levels of pan‐IgG DSA in HLA antibody‐incompatible transplantation. Further investigations are needed to confirm our results.

Effects of weak/non‐complement‐binding HLA antibodies on C1q‐binding

“…However, on the individual patient level, some IgG subclass/epitope‐specificity constellations might result in a synergistic net effect. In this context, it is intriguing that patients having DSA containing all IgG subclasses—and especially with the presence of IgG4—seem to be associated with an increased risk for antibody‐mediated rejection and/or inferior graft survival . Clearly, more studies are required to better understand the biological role of IgG2/4 subclasses directed against HLA molecules in organ transplantation.…”

“…HLA‐antibodies in humans are often polyclonal and contain mixtures of IgG subclasses. Indeed, most DSA contain IgG1/3 as the dominant subclass, and are therefore C‐activating . About half of DSA, however, simultaneously contain IgG2 and/or IgG4.…”

IgG4 donor-specific HLA antibody profile is associated with subclinical rejection in stable pediatric liver recipients

“…Patients with detectable class II DSA, compared to those without, had a higher median (interquartile range) total class II eplet mismatch (33 vs 26 ) and HLA-DQ alone mismatch (12 [8][9][10][11][12][13][14][15][16] vs 8 [4][5][6][7][8][9][10][11][12][13][14][15]). Patients with detectable class II DSA, compared to those without, had a higher median (interquartile range) total class II eplet mismatch (33 vs 26 ) and HLA-DQ alone mismatch (12 [8][9][10][11][12][13][14][15][16] vs 8 [4][5][6][7][8][9][10][11][12][13][14][15]).…”

“…1,2 Nevertheless, and perhaps particularly in liver transplant recipients, high mean fluorescence intensity (MFI) DSA has been observed in the absence of allograft dysfunction or rejection. [6][7][8][9][10][11][12] However, DSA can also injure allografts via antibody dependent cell-mediated cytotoxicity (ADCC) and degranulation of inflammatory cells through the binding of Fc receptors on cytotoxic T and NK cells. High titer class II DSA capable of activating complement (C1q+/IgG3) has shown stronger correlations with rejection and graft loss across all organs when compared to low titer DSA.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…The subclass repertoire is potentially more informative for assessing the pathogenicity of DSAs than complement assays, as subclass predicts complement activation, Fcγ receptor-dependent (FcγR-dependent) functions, and the immunobiology of the alloantibody response. A growing number of reports suggest that characterization of DSA IgG subclass may have utility in identifying patients at risk of rejection or graft loss (5, [55][56][57][58][59][60]. While enlightening, these studies have yet to capture the impact of mixtures of subclasses or multiple concurrent DSA specificities.…”