A prospective study evaluating the role of donor-specific anti-endothelial crossmatch (XM-ONE assay) in predicting living donor kidney transplant outcome

Anti-endothelial cell antibodies (AECAs) may play a role in allograft rejection. We prospectively tested 150 consecutive living donor kidney transplant recipients, with transplants performed at Northwestern Memorial Hospital between January and December 2010, using the donor-specific endothelial (XM-ONE) crossmatch. 88/150 Patients received standard of care (SOC) immunosuppression and analyzed separately, in addition to the complete study cohort. Patients were followed for one year and XM-ONE results were analyzed in relation to occurrence of acute rejection, proteinuria, serum creatinine levels, and biopsy proven fibrosis. No correlation was found between XM-ONE results and protocol or “for-cause” biopsy proven acute rejection or vasculopathy at 12 months. When IgG+ and IgM+ results of the XM-ONE assay were combined, a correlation with proteinuria at 12 months was observed (p = 0.047). Although IgG + XM-ONE results were associated with significantly higher creatinine at 6 months (p = 0.018), significance was lost at 12 months. Conversely, patients with an IgM + XM-ONE crossmatch had significantly lower creatinine at 1 month (p = 0.019), 3 months (p = 0.0045), and 6 months (p = 0.038) post-transplant, but lost statistical significance at 12 months (p = 0.67) post-transplant. In summary, the presence of AECAs as determined by a positive XM-ONE result was not predictive of overall poorer graft outcome after one year in our center.     

HLA class II DQA and DQB epitopes: Recognition of the likely binding sites of HLA-DQ alloantibodies eluted from recombinant HLA-DQ single antigen cell lines

Donor-specific antibodies (DSA) in sera of sensitized transplant patients are often produced against the specific epitopes on mismatched HLA antigens. In this study, we selected sera from 30 kidney transplant patients with DSA and AMR to define DQ epitopes. Using adsorption and elution assays, we identified 18 antibody reaction patterns to define 6 new epitopes and to confirm 12 previously defined epitopes. In one patient case, one mismatched antigen produced 3 different antibodies and, in another, antibodies were produced against the alpha and beta chains of the same antigen. For some sera, a single epitope can explain reactions for 27 of the 29 DQ beads in the single antigen panel.     

Association of genetic polymorphisms of macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) with the detection of donor specific antibodies in kidney allograft recipients

The posttransplant development of donor specific antibodies (DSA) initiates the antibody mediated rejection (AMR), which is associated with the increased rate of graft loss. One of the characteristics of AMR is the infiltration of innate immune system including macrophages, monocytes, neutrophils or NK cells. Macrophage inhibitory factor (MIF) and B-cell activating factor (BAFF) are well known cytokines that are associated with the activation of the innate immune system which can damage kidney allograft. In this article, the association of the genetic polymorphisms of MIF and BAFF with the development of DSA including Class I and II in kidney transplant patients is investigated. A total of 231 renal transplant patients between 2008 and 2012 at St. Vincent Medical Center, CA were studied in a retrospective study design. DSA were determined by Luminex technology, and single nucleotide polymorphisms (SNP) of MIF and BAFF were determined by the real time PCR based on 5′ nuclease allelic discrimination assay. The genetic polymorphisms of MIF rs1007888 (C/T) was associated with increased risk of positive DSA detection (p = 0.04) after transplantation, and consistently significant after 1 year (p = 0.016). Furthermore, the presence of C allele were associated with the increased risk of Class I DSA detection (OR 1.816, CI 1.141–2.889, p = 0.011). Also, genetic polymorphisms of BAFF rs12583006 were associated with the increased risk of Class II DSA detection (p = 0.033). In conclusion, the genetic polymorphisms of MIF and BAFF may increase the risk of posttransplant development of DSA. This result suggests the association between the development of posttransplant DSA and the activation of innate immune system.     

Degree of HLA class II eplet mismatch load improves prediction of antibody-mediated rejection in living donor kidney transplantation

BackgroundHLA mismatching is a well known risk factor for worst outcomes in kidney transplantation.MethodsIn the present study, HLA antigen and eplet mismatches were determined in 151 living donor-recipient pairs transplanted between 2007 and 2014 and rejection episodes and graft survival were evaluated.ResultsWe found that high HLA-II eplet mismatch load (EpMM ≥ 13, versus low EpMM ≤ 5), was an independent predictor of AMR (adjusted HR = 14.839; P = 0.011), while HLA-II AgMM was not. We also showed that HLA-II EpMM load was a significant better predictor of AMR than AgMM (c-statistic = 0.064; P = 0.023). After discriminating HLA-II into HLA-DR and HLA-DQ loci we demonstrated that high versus low eplet mismatch load for HLA-DR (T3 ≥ 6 versus T = 0–1, p = 0.013) and HLA-DQ (T3 ≥ 7 versus T = 0–1, p = 0.009) are independent predictors for AMR.HLA-II EpMM increased discrimination performance of the classical HLA-II AgMM risk model (IDI, 0.061, 95%CI: 0.005–0.195) for AMR. Compared with AgMM, HLA-II eplet model adequately reclassified 13 of 17 patients (76.5%) with AMR and 92 of 134 patients (68.7%) without AMR (cfNRI, 0.785, 95%CI: 0.300–1.426).ConclusionsOur study evidences that eplet-based matching is a refinement of the classical HLA antigen mismatch analysis in LDKT and is a potential biomarker for personalized assessment of alloimmune risk.     

Role of antibodies to self-antigens in chronic allograft rejection: Potential mechanism and therapeutic implications

Significant progress has been made in preventing acute allograft rejection following solid organ transplantation resulting in improved allograft survival. However, long term function still remains disappointing primarily due to chronic allograft rejection. Alloimmune responses primarily defined by the development of antibodies (Abs) to donor mismatched major histocompatibility antigens during the post-transplantation period have been strongly correlated to the development of chronic rejection. In addition, recent studies have demonstrated an important role for autoimmunity including the development of Abs to organ specific self-antigens in the pathogenesis of chronic allograft rejection. Based on this, a new paradigm has evolved indicating a possible cross-talk between the alloimmune responses and autoimmunity leading to chronic rejection. In this review, we will discuss the emerging concept for the role of cellular and humoral immune responses to self-antigens in the immunopathogenesis of chronic allograft rejection which has the potential to develop new strategies for the prevention and/or treatment of chronic rejection.