The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes.

Background: Anti-HLA-DQ antibodies are the predominant HLA class II donor-specific antibodies (DSAs) after transplantation. Recently, de novo DQ DSA has been associated with worse allograft outcomes. The aim of this study was to determine the further complement-binding characteristics of the most harmful DQ DSA.

Incidence and impact of de novo donor-specific alloantibody in primary renal allografts.

Background: To date, limited information is available describing the incidence and impact of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes.

Methods: The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006.

Predicting operational tolerance in pediatric living-donor liver transplantation by absence of HLA antibodies.

Background: The role of anti-human leukocyte antigen (HLA) antibodies in operational tolerance (OT) after pediatric living-donor liver transplantation (LDLT) remains inconclusive. We investigated whether the presence of HLA antibodies impeded the development of OT.

Methods: We retrospectively examined the prevalence of anti-HLA antibodies in pediatric LDLT recipients before transplantation and at 3 weeks after transplantation and analyzed the significance of those antibodies in relation to later OT.

Antibodies to HLA-E may account for the non-donor-specific anti-HLA class-Ia antibodies in renal and liver transplant recipients.

The non-donor-specific anti-HLA-Ia antibodies correlate significantly with lower graft survival in organ transplant patients. Based on our earlier findings that anti-HLA-E murine monoclonal antibodies (MEM-E/02 and 3D12) reacted with different HLA-Ia alleles and the peptides shared by HLA-E and HLA class, Ia alleles inhibited the HLA-Ia reactivity of the anti-HLA-E antibodies in normal non-alloimmunized males, the possibility of that anti-HLA-E IgG may account for the non-donor-specific anti-HLA-Ia antibodies in the allograft recipients was examined by multiplex-Luminex®-immunoassay. About 73% of renal and 53% of liver transplant patients' sera with high level of anti-HLA-E IgG showed reactivity to different non-donor HLA-Ia alleles.

A report of the epidemiology of de novo donor-specific anti-HLA antibodies (DSA) in "low-risk" renal transplant recipients.

The donor specific anti-HLA antibody (DSA) has been increasingly recognized as the major cause of allograft loss. Despite this, no published reports exist describing the true epidemiology of de novo DSA.Here we describe the epidemiology of DSA based on the results of one of the longest running antibody study in consecutive renal transplant recipients.

Factors affecting outcomes of liver transplantation: an analysis of OPTN/UNOS database.

This was a historic cohort analysis based on 110,521 patients who underwent liver transplant between 1987 and July 2011 in the United States and were reported to the UNOS registry. In addition to univariate Kaplan-Meier survival analyses, we used cox proportional hazard analysis and multiple logistic regression analysis to evaluate hazard ratios adjusted for clinical factors. The overall 5- and 10-year patient survival rates were 81% and 72%, respectively, for 4,412 recipients of living donor livers and 73% and 59%, respectively, for 106,109 recipients of deceased donor livers.

HLA-E monoclonal antibodies recognize shared peptide sequences on classical HLA class Ia: relevance to human natural HLA antibodies.

The non-classical HLA-Ib molecule, HLA-E share several peptide sequence similarities with the heavy chains of classical HLA class Ia (-B and -C) molecules. Therefore, the antibodies to HLA-E, that recognize shared sequences, may bind to HLA-Ia alleles. This hypothesis is tested by examining the affinity of HLA-E monoclonal antibodies (HLA-E-MAbs) to HLA-Ia molecules and by inhibiting the antibody binding to both HLA-E and HLA-Ia with the shared peptide sequence(s).

No occurrence of de novo HLA antibodies in patients with early corticosteroid withdrawal in a 5-year prospective randomized study.

The purpose of this study was to determine the effect of early corticosteroid cessation on the occurrence of de novo human leukocyte antigen (HLA) antibody posttransplant. Renal transplant recipients (n=37) were randomized to early corticosteroid withdrawal at day 7 posttransplant (n=21 patients), or to chronic steroids (n=16), all in combination with thymoglobulin as induction agent, tacrolimus and mycophenolic acid as maintenance therapy. To establish the time course of HLA antibody appearance, sera collected pretransplant and for up to 5 years posttransplant were screened for the appearance of HLA antibodies.

Human leukocyte antigen class II DQ alpha and beta epitopes identified from sera of kidney allograft recipients.

Background: Epitopes are the sites to which antibodies bind. Both alpha and beta peptide chains of the human leukocyte antigen-DQ heterodimers (DQA1 and DQB1, respectively) contain polymorphic regions. We can identify DQA1 and DQB1 epitopes by DQ single antigen beads assay of the antibodies, correlating the beads' reaction patterns with either DQA1 or DQB1 alleles.

Reappraisal of HLA antibody analysis and crossmatching in kidney transplantation.

It has been established that preformed IgG antibodies specific for donor HLA antigens may accelerate graft failure. An increasing number of studies have demonstrated adverse graft survival in patients who have anti-HLA antibodies, whether preformed or developed post-transplant. More recently, ELISA and flow cytometric techniques were introduced to overcome the limited sensitivity and specificity of the CDC assay.

HLA class II DP epitopes.

Both alpha (DPA1) and beta (DPB1) peptide chains of class II HLA-DP heterodimers contain polymorphic regions. Five DPB1 epitopes, for which we propose numbers #4001-4005, were identified by the reaction patterns ofthe DPB1 antibodies to DPB1 alleles of DP single antigen beads. Epitopes were defined by unique amino acids shared by the positive antigens of theantibodies.

Epitopes of the HLA-A, B, C, DR, DQ and MICA antigens.

The intent for this chapter was to summarize the HLA epitopes that have been defined by adsorption and elution of antibodies from single HLA antigens to date. Examples of reactions of mAb and eluted allosera with the class I, class II and MICA SA are also presented. We have identified 103 HLA class I epitopes, of which 40 were defined by mAbs and 63 by alloantibodies mostly eluted from rHLA class I single antigen cell lines.

Retrospective antibody analysis of thirty patients with kidney graft failure.

Out of 30 patients who rejected their kidney grafts, HLA or MICA antibodies were found in 26 patients. Among the four patients in whom antibodies could not be found, two patients did not have any HLA mismatch with their mother donor, and 1 had died with a functioning graft. There was only one other patient who chronically rejected but did not have antibodies.

Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience.

1. From the analysis of 266 Greenville kidney recipients, we found that almost every patient who had graft failure had HLA antibodies (93%), while less than half of patients with currently functioning graft had antibodies (46%). 2.

Clinical and anti-HLA antibody profile of nine renal transplant recipients with failed grafts: donor-specific and non-donor-specific antibody development.

This study applied the single antigen microsphere technology to the retrospective analysis of sequential post-transplant serum samples in the context of the patient's clinical course. Detailed information on nine of the study patients was presented as representative of the larger cohort and illustrative of different patterns of anti-HLA antibody development and different clinical scenarios that culminated in graft failure. Our major observations are summarized as follows: 1.

Lung transplantation in the United States: 1990-2005.

The number of lung transplants reported to the OPTN/UNOS Registry has been increasing during the past 15 years. The increase is mainly due to a steady increase in transplants in the 50-64 age group. There is also a trend toward increasing lung transplants for older patients (> 65 yr) since 2001.

Liver transplantation in the United States.

Based on the data reported to the OPTN/UNOS Liver Transplant Registry between 1987-2005, we found: 1. The number of deceased-donor liver transplantations increased slowly each year, with most of the increase being in adult recipients. The number of LD transplants, on the other hand, decreased sharply after 2002, following 3 years of rapid increase from 1998-2001 in both pediatric and adult recipients.

Association of kidney transplant failure and antibodies against MICA.

Despite the progress in renal transplantation, acute rejection and graft failure still occur and chronic rejection continues to be the main problem in long-term allograft survival. Although kidney transplant rejection has been linked to anti-HLA antibodies, not all patients with failed kidney transplants have anti-HLA antibodies, indicating that other loci may be involved. Sera of 63 patients who experienced kidney rejection were compared against sera of 82 patients with functioning transplants.

Frequency of MIC antibody in rejected renal transplant patients without HLA antibody.

Antibodies to MICA and MICB antigens were sought in the sera of 139 kidney transplant recipients. MICA*001, *002, *007, *008, and MICB*002 antigens were produced in Escherichia coli and then tested using enzyme-linked immunosorbent assay plates. Among 35 normal sera, 6% had MIC antibodies, and among 14 sera from pregnant women, 21% had MIC antibodies.

Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial.

In this large collaborative study, 2,231 transplanted patients with functioning kidneys were tested for HLA antibodies, then examined 2 years later for graft survival. Among 478 patients with antibodies, 15.1% failed in 2 years, compared to 6.

Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure.

The role of HLA antibodies in chronic allograft rejection was examined utilizing a unique resource of sera collected annually and stored over a 12-year period from patients with rejected or retained grafts. In patients selected for not having preformed HLA antibodies, 679 postoperative serial serum samples from 39 patients who rejected their grafts and 26 with functioning grafts were tested for HLA Class I and Class II antibodies by flow cytometry and for MICA antibodies by cytotoxicity on recombinant cell lines. HLA antibodies were found in 72% of patients who rejected grafts, compared to 46% with functioning transplants (p<0.

Predicting kidney graft failure by HLA antibodies: a prospective trial.

HLA antibodies have been shown to be associated with late graft loss of organ transplants in prior studies. Recently they were even shown to appear years BEFORE rejection. (1) An international cooperative study of 4763 patients from 36 centers was undertaken to determine the frequency of HLA antibodies in patients with functional transplants.