Development Of Human Leukocyte Antigen Antibodies Research Articles

Does temporary mechanical circulatory support with Impella 5.5 induce de novo human leukocyte antigen antibodies production in heart transplantation candidates?

Little is known about de novo human leukocyte antigen (HLA) antibody development with Impella 5.5 temporary mechanical circulatory assist support and downstream effects following heart transplantation in the new heart allocation system. 13 Impella and 17 control patients without device support were prospectively enrolled between December 2020 and June 2022. HLA antibodies with calculated panel reactive antibodies (cPRA) were assessed pre- and post-device implantation and within 1-year post-heart transplantation. Baseline prevalence of HLA antibodies and median cPRA were similar between groups. Patients in the study arm were on Impella support for a median of 7 days. No significant differences in HLA antibodies were observed post-device or post-heart transplant. One patient in the Impella arm developed rejection and required treatment. One Impella patient died due to infection and one control patient died due to primary graft dysfunction. Short-term use of Impella 5.5 in the new heart allocation system does not appear to increase risk of de novo HLA antibody development. Further studies are needed to validate these preliminary findings.

Peptides Derived From Mismatched Paternal Human Leukocyte Antigen Predicted to Be Presented by HLA-DRB1, -DRB3/4/5, -DQ, and -DP Induce Child-Specific Antibodies in Pregnant Women.

Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers’ presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters’ binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.

Impact of Degree Of Human Leucocyte Antigen Mismatch on Live Donor Kidney Transplant Recipients

Background: The human leukocyte antigen (HLA) system plays a crucial role in the activation and function of the immune system. HLA mismatches may lead to activation of alloreactive T-cells and development of donor-specific HLA antibodies (DSA), thereby significantly impairing kidney graft survival. Methods: From March 1976 and August 2019, a total of 2200 kidney transplant recipients were included in the study.The patients were divided into 3 main groups according to degree of HLA mismatch.Results: acute rejection episodes were more frequent with group II and III. Chronic rejection was revealed in graft biopsies of group II and III more than group I . Incidence of post-transplant Hypertension and Diabetes mellitus was higher in group III . Median serum creatinine was higher in group III after 2, 3, 4 and 5 years post transplantation with subsequent lower creatinine clearance .The majority of patients were alive with functioning graft at last follow-up especially in group I . More patients were alive with failed graft at last follow up in group III.. On the other hand the 5, 10 and 15 years graft and patient survival showed statistical significant difference among the 3 groups with better survival for group I.Conclusions: The degree of mismatch affected the choice of immunosuppressive regimen. Higher HLA mismatch was associated with higher incidence of diabetes and hypertension and lower patient and graft survival.

Sensitization during short-term mechanical circulatory support. Determinants, therapeutic management, and outcomes after heart transplant

Introduction and objectivesThe development of human-leukocyte antigen antibodies is a well-known adverse effect of the use of long-term ventricular assist devices (VADs). The aim of this study was to determine the incidence of sensitization during short-term mechanical circulatory support with VAD (CentriMag), its determinants, and its impact on posttransplant outcomes. MethodsWe performed a retrospective review of patients who were bridged to transplant with short-term VAD from 2009 to 2019. Sensitization was defined as a calculated panel-reactive antibody> 10%. The endpoints included overall survival and rejection-free survival. ResultsA total of 89 patients (median age 56.0 [interquartile range, 50.0-59.9] years, 16.8% female) received a short-term VAD as a bridge to transplant. The median duration of support was 23.6 [interquartile range, 16.6-35.0] days. Eleven patients (12.4%) became sensitized during support. The only factor significantly associated with sensitization was female sex (OR, 8.67; 95%CI, 1.93–38.8; P=.005). Of the 89 patients, 21 patients died during support; 68 patients underwent heart transplant. After a mean follow-up of 49.6 ±31.2 months, 8 patients (11.8%) died and 20 (29.4%) had at least 1 rejection episode. On multivariate analysis, sensitization was an independent predictor of acute rejection (HR, 3.64; 95%CI, 1.42-9.33; P=.007), with a nonstatistically significant trend to higher mortality (HR, 4.07; 95%CI, 0.96-17.3; P=.057). ConclusionsSensitization with short-term VADs can occur and is significantly associated with female sex and with rejection. Sensitization also showed a nonstatistically significant trend to higher mortality.

Sensibilización durante la asistencia circulatoria de corta duración. Determinantes, tratamiento y pronóstico después del trasplante cardiaco

Introduction and objectivesThe development of human-leukocyte antigen antibodies is a well-known adverse effect of the use of long-term ventricular assist devices (VADs). The aim of this study was to determine the incidence of sensitization during short-term mechanical circulatory support with VAD (CentriMag), its determinants, and its impact on posttransplant outcomes. MethodsWe performed a retrospective review of patients who were bridged to transplant with short-term VAD from 2009 to 2019. Sensitization was defined as a calculated panel-reactive antibody> 10%. The endpoints included overall survival and rejection-free survival. ResultsA total of 89 patients (median age 56.0 [interquartile range, 50.0-59.9] years, 16.8% female) received a short-term VAD as a bridge to transplant. The median duration of support was 23.6 [interquartile range, 16.6-35.0] days. Eleven patients (12.4%) became sensitized during support. The only factor significantly associated with sensitization was female sex (OR, 8.67; 95%CI, 1.93–38.8; P=.005). Of the 89 patients, 21 patients died during support; 68 patients underwent heart transplant. After a mean follow-up of 49.6 ±31.2 months, 8 patients (11.8%) died and 20 (29.4%) had at least 1 rejection episode. On multivariate analysis, sensitization was an independent predictor of acute rejection (HR, 3.64; 95%CI, 1.42-9.33; P=.007), with a nonstatistically significant trend to higher mortality (HR, 4.07; 95%CI, 0.96-17.3; P=.057). ConclusionsSensitization with short-term VADs can occur and is significantly associated with female sex and with rejection. Sensitization also showed a nonstatistically significant trend to higher mortality.

Critical evaluation of a possible role of HLA epitope matching in kidney transplantation.

Human leukocyte antigen (HLA) matching is one of the cornerstones of organ allocation in deceased-donor kidney transplantation. Increased numbers of HLA allele mismatches are associated with a higher risk of immunological rejection, de novo donor-specific HLA antibody development and graft failure. HLA epitopes are defined as the specific portions of HLA molecules to which antibodies and T-cell receptors bind with their paratopes. The same epitope can be present on different HLA alleles. Therefore, HLA matching at the epitope instead of allele level theoretically offers a more precise assessment of donor-recipient HLA compatibility and may more effectively prevent sensitization against foreign tissue. In this review, we describe the different options proposed to define clinically relevant HLA epitopes and critically discuss the potential role of HLA epitope matching in kidney transplantation.

HLA Alloimmunization Following Ventricular Assist Device Support Across the Age Spectrum.

Ventricular assist device (VAD) therapy has become an important tool for end-stage heart failure. VAD therapy has increased survival but is associated with complications including the development of human leukocyte antigen (HLA) antibodies. We sought to determine the incidence of HLA antibody development post-VAD insertion, across the age spectrum, in patients receiving leukocyte-reduced blood products, with standardized HLA antibody detection methods and to investigate factors associated with antibody development. This was a retrospective analysis of all patients who underwent durable VAD placement between 2005 and 2014. Inclusion criteria included availability of pre- and post-VAD HLA antibody results. Associations between HLA antibody development in the first-year postimplant and patient factors were explored. Thirty-nine adult and 25 pediatric patients made up the study cohort. Following implant, 31% and 8% of patients developed new class I and class II antibodies. The proportion of newly sensitized patients was similar in adult and pediatric patients. The class I HLA panel reactive antibody only significantly increased in adults. Pre-VAD sensitization, age, sex (pediatrics), and transfusion were not associated with the development of HLA antibodies. In a cohort of VAD patients receiving leukocyte-reduced blood products and standardized HLA antibody testing, roughly one-third developed new class I antibodies in the first-year postimplant. Adults showed significantly increased class I panel reactive antibody following VAD support. No patient-related factors were associated with HLA antibody development. Larger prospective studies are required to validate these findings and determine the clinical impact of these antibodies following VAD insertion.

OR50 Donor specific HLA antibody formation following distal tibial allograft and subsequent graft resorption: A case report

Background The association between donor specific Human Leukocyte Antigen (HLA) antibody formation and small bone allograft resorption has not been studied. We present the case of a patient treated for glenoid bone loss with a distal tibial allograft who formed donor specific HLA antibodies against the allograft and had subsequent graft resorption. Methods The patient received a right glenoid reconstruction using distal tibia allograft with Bankart repair in June 2015. X-ray and CT-Scans were performed pre-and post-surgery at standard checkpoints. Patient blood and serum samples were collected pre-and-post-surgery for HLA typing and HLA antibody testing. Results Pre-operative CT scans revealed large Hill-Sachs and bony Bankart lesions, and pre-operative HLA antibody testing revealed no HLA antibodies. The 2-week post-operative radiograph revealed proper graft fixation, and the patient had good range of motion 6-weeks post-surgery. However, 6-week post-operative HLA antibody testing revealed development of donor specific HLA antibodies directed at HLA-A2 antigen as well as several antigens belonging to the A2 crossreactive group (A24, A68, A69, B57 and B58), cPRA of 69%. Eplet analysis showed reactivity to 62GE and 151AHV eplets. At 3-months post-surgery, the patient was weak in internal rotation, and the HLA-A2 antibodies continued to be detected at 5-months post-surgery. Shortly after the antibody peak, the 6-month post-operative CT arthrogram revealed significant graft resorption. Interestingly, the donor specific HLA-A2 antibodies were undetectable 6 months after resorption was complete. Discussion This case report shows that small bone allografts can lead to HLA sensitization. The temporal correlation between donor specific HLA antibody formation and clinical findings strongly suggest an association between HLA antibody formation and graft resorption. It is unclear what impact HLA antibody formation may have on future regrafting in this patient. This case shows a clear association between the formation of donor specific HLA antibodies and graft resorption, which suggests a link between the two events. Our future studies will address the frequency of HLA antibody formation, and investigate whether tissue processing techniques could be improved to reduce bone allograft antigenicity.

HLA sensitisation: can it be prevented?

Human leukocyte antigen (HLA) sensitisation occurs after transfusion of blood products and transplantation. It can also happen spontaneously through cross-sensitisation from infection and pro-inflammatory events. Patients who are highly sensitised face longer waiting times on organ allocation programmes, more graft rejection and therefore more side effects of immunosuppression, and poorer graft outcomes. In this review, we discuss these issues, along with the limitations of modern HLA detection methods, and potential ways of decreasing HLA antibody development. We do not discuss the removal of antibodies after they have developed.

Red cell and human leukocyte antigen alloimmunization in candidates for renal transplantation: a reality

Red cell and human leukocyte antigen alloimmunization in candidates for renal transplantation: a reality

Cyclosporine or Tacrolimus: Which Is the Better Partner for Myfortic or CellCept?

BackgroundMycophenolic acid (MPA) pharmacokinetics using the mycophenolate mofetil (CellCept) formulation are known to differ between patients receiving tacrolimus (FK) or cyclosporine (CyA), but only limited data exist concerning concomitant use of FK or CyA with enteric-coated mycophenolate sodium (EC-MPS; Myfortic). This retrospective study compared the drug interactions with the mycophenolic acid blood levels using different immunosuppressants and their relation to graft survival. Patients and methodsWe studied MPA levels in posttransplant sera from 298 renal transplant recipients. ResultsPatients receiving immunosuppression with CyA + Myfortic showed 94% at 5- and 10-year graft survivals, which were better than CyA + CellCept (75%, 63%). This combination suppressed posttransplant human leukocyte antigen (HLA) antibody development significantly (P = .03) with higher MPA levels. ConclusionPatients immunosuppressed with CyA + Myfortic showed higher MPA levels and lower posttransplant HLA antibody development as well as the best graft survival. CyA + Myfortic or FK + Cellcept may be better combinations.

The Clinical Significance of Human Leukocyte Antigen Antibody Development in Kidney Transplantation

BackgroundThis retrospective study uses the LAT-M (One Lambda Inc., Calif) screen assay to reexamine the impacts (a), of pretransplant human leukocyte antigen (HLA) antibody on long-term graft survival; (b) posttransplant HLA antibody on long-term graft survival and (c) immunosuppressive regimen on posttransplant HLA antibody development. Patients and methodsPretransplant sera from 222 renal transplant recipients and posttransplant sera from 216 renal transplant recipients were studied for the impact of HLA antibody on long-term graft survival. ResultsAmong the patients who did not display pretransplant HLA antibodies, 85% enjoyed 5-year and 59% 10-year graft survival, whereas the patients who tested positive were 83% and 83% (P = .5596). Among the patients who did not show posttransplant HLA antibodies, 99% enjoyed 5-, 91% 10-, and 65% 15-year graft survival, whereas for the 44 patients who tested positive they were 59%, 44%, and 30%, respectively (P < .0001). Patients prescribed cyclosporine + myfortic (odds ratio 0.17, P = .05) or FK + Cellcept (odds ratio 0.36, P = .04) showed the lowest posttransplant HLA antibody development. ConclusionBoth regimens improve graft survival.

Relationship of donor HLA antibody strength to the development of transfusion‐related acute lung injury

Antibodies against the human leukocyte antigen (HLA) in donors' blood are implicated in the development of transfusion-related acute lung injury (TRALI). Screening of female donors for HLA antibodies has been introduced to prevent TRALI; however, the relationship of HLA antibody strength in the transfused components to the development of TRALI has not been evaluated in detail. Donors involved in 1038 cases of nonhemolytic transfusion reactions (NHTRs) including 283 cases of TRALI were screened for HLA antibodies by the fluorescence beads method. HLA antibody specificity and strength were analyzed in detail. The usefulness of enzyme-linked immunosorbent assay (ELISA) for screening HLA antibodies was also evaluated. Among 21 cases of TRALI, four cases of possible TRALI, and five cases of other NHTRs, the sum of mean fluorescence intensity (MFI) of donors' HLA antibodies to patients' cognate antigen(s) was determined in 18, four, and three cases, respectively. The sum of MFI in TRALI cases was significantly higher than that in other NHTR cases (p<0.05). When HLA antibody-positive samples were reevaluated by ELISA, the ELISA optical density ratio was significantly higher in donors' samples associated with TRALI than in those associated with other NHTRs (p<0.01) A correlation between the HLA antibody strength and development of TRALI was indicated. The antibody strength measured by ELISA could be used as the basis for the screening of HLA antibodies in place of the fluorescence beads method. This study provided clues to the establishment of a cutoff value for HLA antibody screening in an evidence-based manner for the prevention of TRALI.

Antibodies to Self-Antigens Predispose to Primary Lung Allograft Dysfunction and Chronic Rejection

Primary graft dysfunction (PGD) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Here, we report that preformed antibodies to self-antigens increase PGD risk and promote BOS. Adult lung transplant recipients (n = 142) were included in the study. Primary graft dysfunction and BOS were diagnosed based on International Society for Heart and Lung Transplantation guidelines. Antibodies to self-antigens k-alpha-1 tubulin, collagen type V, and collagen I were quantitated using standardized enzyme-linked immunosorbent assays, and cytokines were analyzed using Luminex immunoassays (Biosource International, Camirillo, CA). Human leukocyte antigen (HLA) antibodies were measured using Flow-PRA (One Lambda, Canoga Park, CA). Lung transplant recipients with pretransplant antibodies to self-antigens had increased risk of PGD (odds ratio 3.09, 95% confidence interval: 1.2 to 8.1, p = 0.02) compared with recipients without. Conversely, in patients with PGD, 34.7% were positive for pretransplant antibodies whereas in the PGD negative group, only 14.6% had antibodies (p = 0.03). Antibody positive patients demonstrated high levels of proinflammatory cytokines interleukin (IL)-1β (2.1-fold increase), IL-2 (3.0), IL-12 (2.5), IL-15 (3.0), and chemokines interferon-inducible protein-10 (3.9) and monocyte chemotactic protein-1 (3.1; p < 0.01 for all). On 5-year follow-up, patients without antibodies showed greater freedom from development of HLA antibodies compared with patients who had antibodies (class I: 67% versus 38%, p = 0.001; class II: 71% versus 41%, p < 0.001). Patients with pretransplant antibodies were found to have an independent relative risk of 2.3 (95% confidence interval: 1.7 to 4.5, p = 0.009) for developing BOS. Presence of antibodies to self-antigens pretransplant increases the risk of PGD immediately after transplant period and BOS on long-term follow-up. Primary graft dysfunction is associated with an inflammatory cascade that augments the alloimmune (anti-HLA) response that predisposes to BOS.