Pre-Transplant IgG Reactivity to Apoptotic Cells Correlates With Late Kidney Allograft Loss.

Abstract

Pre-existing serum antibodies have long been associated with graft loss in transplant candidates. While most studies have focused on HLA-specific antibodies, the contribution of non-HLAreactive antibodies has been largely overlooked. We have recently characterized monoclonal antibodies secreted by B cell clones derived from kidney allograft recipients with rejection that selectively bind to apoptotic cells. Here, we assessed the presence of such antibodies in pretransplant serum from 300 kidney transplant recipients and examined their contribution to the graft outcomes. Kaplan-Meier survival analysis revealed that patients with high pre-transplant IgG reactivity to apoptotic cells had a significantly increased rate of late graft loss. The effect was only apparent after approximately 1 year post-transplant. Moreover, the association between pretransplant IgG reactivity to apoptotic cells and graft loss was still significant after excluding patients with high reactivity to HLA. This reactivity was almost exclusively mediated by IgG1 and IgG3 with complement fixing and activating properties. Overall, our findings support the view that IgG reactivity to apoptotic cells contribute to pre-sensitization. Taking these antibodies into

Innate-like self-reactive B cells infiltrate human renal allografts during transplant rejection

“…These serum autoantibodies can mediate vascular injury and accelerate graft rejection 84 . However, they are present prior to transplantation and therefore are likely natural antibodies 85 . In contrast, intrarenal Bin cells expressed highly mutated IgG autoantibodies that did not bind vascular endothelium.…”

Natural Antibodies Are Associated With Rejection and Long-term Renal Allograft Loss in a Multicenter International Cohort

“…Previous work from our laboratory showed that pretransplant Nabs were elevated in patients who later developed AMR. 10 In our present study, multivariable logistic regression models, depicted in Figure 2 and Figure S5 ( SDC , http://links.lww.com/TP/C651), showed that elevated pretransplant Nabs were not significantly associated with the risk of developing all AMRs (including AMR in mixed rejection profiles; OR 1.22, P = 0.4398). Pretransplant Nabs were not significantly associated with the risk of developing AMR alone (ie, excluding mixed rejection profiles; OR 1.08, P = 0.7726; not shown).…”

“…9 We have previously described Nabs in the context of kidney and heart transplantation. Elevated Nabs detected before transplantation were associated with increased graft loss after kidney transplantation 10 as well as primary graft dysfunction in heart transplant recipients. 11 Elevated Nabs were also observed in kidney transplant patients undergoing active antibody-mediated rejection (AMR).…”

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

“…It has been demonstrated that these autoantibodies can mediate vascular injury and accelerate graft rejection (Cardinal et al, 2013). Many of these antibodies are thought to be natural antibodies, present prior to transplantation, titers of which predict subsequent graft loss (Gao et al, 2014). In contrast, our results demonstrate that intra-renal B cells express highly mutated IgG autoantibodies which bound renal antigens.…”