6OR A case of rejection in 10/10 allele matched transplant with “high titer low avidity” HLA-DP donor specific antibodies (original) (raw)
Human Immunology, 2018
Despite advances in HLA matching, graft failure remains a serious complication after allogeneic hematopoietic cell transplantation (HCT). Pre-formed anti-HLA donor-specific antibodies (DSAs) have been associated with graft failure, but the impact of newly developing (de novo) anti-HLA antibodies on HCT outcomes remains unknown. Here, we present the first reported case of graft failure associated with de novo anti-HLA-DPB1 DSA after a 10/10 matched unrelated donor HCT. Based on this observation, testing for DSA should be considered in case of unexplained pancytopenia after allogeneic transplantation, especially after reduced intensity conditioning.
Transplantation and Cellular Therapy, 2023
Background. The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Methods. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. Results. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively. Conclusions. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.
Transplantation Proceedings, 2018
The presence of isolated de novo anti-DP antibodies is uncommon, making it difficult to determine the impact of anti-DP antibodies on graft outcome. We describe a case of acute antibody-mediated rejection mediated by de novo donor-specific anti-HLA-DP antibodies. Furthermore, the generation of non-donorspecific anti-DP antibodies (NDSAs) detected in the patient's sera was investigated. An 18-year-old woman with pre-transplant PRA 0% received kidney transplantation from a living donor. She experienced combined acute T-cell-mediated and antibody-mediated rejection at 15 months after transplantation. High resolution HLA typing of the donor and the patient revealed that they were mismatched at both DPB1 (DPB1*31:01) and DPA1 (DPA1*02:02) loci. The single antigen bead (SAB) testing of patient's sera revealed antibodies against donor's DPB1*31:01 and DPA1*02:02 alleles. Antibodies against several non-donor-specific DP antigens were also detected. No antibodies against other HLA class I and II antigens were detected. In order to explain the reactivity pattern of NDSAs, HLAMatchmaker program was used to identify immunizing eplets shared between donor alleles and reactive beads. The analysis showed 84DEAV, a DPB1 eplet, as a shared eplet found on DPB1*31:01 (mismatched donor allele) and on DPB1 reactive alleles in SAB assay. Additionally, 50RA, a DPA1 eplet, was identified as a shared eplet found on DPA1*02:02 (mismatched donor allele) and on DPA1 reactive alleles in SAB assay. This case highlights the clinical significance of HLA-DP antibodies. Furthermore, the generation of NDSA anti-DP antibodies by epitope sharing underscores the importance of HLA-DP epitope matching in kidney transplantation. Highlights • This is a case of antibody-mediated rejection by de novo donor-specific anti-HLA-DP antibodies. • Antibodies against several non-donor-specific DP antigens were also detected. • The eplets shared between donor alleles and reactive beads were identified. • The epitope sharing between HLA-DP alleles was highlighted.
Role of de novo donor-specific anti-HLA antibodies in kidney graft failure: A case-control study
HLA, 2017
The role of de novo donor-specific anti-HLA antibodies (dnDSA) within the pathways leading to graft failure remains not fully understood. We investigated 56 patients who were transplanted between 2002-2014 with kidney graft failure (cases), for a possible association of development of dnDSA with graft failure. The 56 patients with failed transplants were matched with 56 patients with a functioning graft at present for the variables deceased or living donor, transplant number, transplant year, recipient age and gender, donor age and gender, dialysis vintage time, transplant induction therapy. All patients had at least one serum collected 1 year before failure (in cases) or end of follow-up (in controls). Cases and controls were very well-matched in several baseline characteristics. Post-transplant anti-HLA antibodies were found in 84% of cases and only 36% of controls (P<0.001), with 54% of cases and 16% of controls (P<0.001) having dnDSA at time of detection. Chronic active antibody-mediated rejection was significantly more common (P<0.001) in patients with dnDSA (61% vs. 12%), in 53 (47%) patients that had at least 1 graft biopsy performed during follow-up. dnDSA was a significant risk factor (OR=6.06; P=0.003) for graft failure in a multivariable conditional logistic regression model. dnDSA as a time-dependent variable, was also an independent predictor (HR=2.46; P=0.002) of graft failure in a multivariable Cox regression analysis. In both statistical approaches, only dnDSA-II (OR=11.90; P=0.006) (HR=2.30; P=0.014) was significantly associated with graft failure. Post-transplant dnDSA was clearly associated with graft loss, particularly if against HLA class II antigens. dnDSA detection should be a tool for post-transplant monitoring of kidney graft recipients, allowing for the identification of those with a higher risk of graft failure.
Transplantation, 1998
A single-center study of 655 nonsensitized recipients of primary cadaveric kidney grafts is presented. Graft survival in serologically HLA-DR 1-10 antigen-matched grafts to nonsensitized recipients at 1 year was 90%, compared with 82% (P=0.004) and 73% (P=0.001) in one and two DR antigen-mismatched grafts. The corresponding figures at 5 years were 76%, 62%, and 56%, respectively. Matching for the DR antigens 11-14, or for some DR alleles only detectable by genomic typing, further improved graft survival, but the differences did not reach statistical significance. Matching also for the serologically defined HLA-A and -B antigens did not significantly further improve overall graft survival, but some effects for grafts surviving at least 1 year were observed. Among recipients of grafts mismatched for zero, one, or two HLA-DR antigens, acute rejection episodes were experienced in 48%, 64% (P<0.001), and 82% (P<0.001), respectively, within the first 3 months. HLA-A and -B mismatches showed no significant correlation to acute rejection episodes. Matching for the DR antigens 1-10 significantly secures and prolongs the survival of first cadaveric renal grafts. Our results also show that DR 1-10 antigen-matched combinations can often be obtained even in rather small recipient pools, when actively sought for.
Tissue Antigens, 2009
As part of the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), seven centers participated in a collaborative project to determine whether any significant humoral sensitization occurred post-transplant among recipients of HLA partially mismatched hematopoietic cell transplants (HCTs). A total of 140 donor/recipient pairs were enrolled with a total of 367 pre-and post-transplant sera analyzed. The majority of the samples (69.1%) were obtained within 30-90 days post-HCT. HLA-specific antibodies were defined using single antigen bead assays on a Luminex™ platform with a positive cutoff value of 1000 normalized median fluorescence intensity (MFI). There was an overall incidence of post-HCT sensitization toward donor HLA mismatches of 5.7%; however, all cases were among recipients of one HLA haplotype-mismatched grafts under nonmyeloablative, pre-transplant conditioning. Among the one haplotype-mismatched recipients, 15.7% (8/51) developed donor HLA-specific antibodies and 29.4% also had antibodies directed toward third party HLA antigens. Among the donor-specific antibodies, 9.8% were directed toward HLA class I antigens; 7.8% were against class II antigens; and 2.0% had both class I and II specificity. The relative strength of post-transplant antibodies was low with no significant difference in the mean maximum MFI values between third party and donor-specific antibodies. Because only a small number (10.2%) of the post-transplant samples were obtained 180 days or more post-HCT, longer term study is needed to evaluate any clinical relevance of these low-to-moderate levels of donor-specific antibody in one haplotypemismatched recipients, as well as to determine whether any other antibodies occur at later times.
Clinical importance of non-HLA antibodies in solid organ transplantation
Current Opinion in Organ Transplantation, 2006
Purpose of review The clinical importance of HLA-specific antibodies for organ allograft outcome is well established. Antibody-mediated rejections of HLA-identical kidney transplants and rejections in the absence of detectable HLA antibodies, however, indicate that non-HLA antibodies also play a significant role. Recent findings Non-HLA antigens, such as the polymorphic major histocompatibility complex class I-related chain A, expressed on endothelial cells, have been implicated in the pathogenesis of hyperacute, acute, and chronic organ allograft rejections. The use of donor endothelial cells as targets in pretransplant and posttransplant cross-matches will facilitate detection and specificity determination of other clinically relevant non-HLA antibodies. Non-swine leukocyte antigen-antibody responses are also receiving increasing interest as important mediators of acute vascular rejection of porcine organ xenografts; acute vascular rejection is the next big hurdle preventing clinical xenotransplantation. Summary Non-HLA antibody responses are receiving increasing interest in acute and chronic rejection, and specificity, affinity, and pathogenicity need to be investigated to estimate their contribution. This review summarizes past and current knowledge of the clinical importance and specificities of non-HLA antibodies and mechanisms by which these antibodies may contribute to graft destruction in organ allotransplant and xenotransplant recipients.