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BACKGROUND: Donor-specific antibodies (DSAs) targeting human leukocyte antigens (HLAs) substantially reduce the longevity of transplanted organs. Desensitization of DSA-positive renal transplant recipients is achieved through intravenous administration of immunoglobulin (IVIg). However, the presence and detectability of anti-HLA antibodies in IVIg preparations following administration are not fully understood. We aimed to assess whether immunoglobulin preparations contain anti-HLA antibodies that can be detected as passive antibodies when administered into the body. METHODS: We evaluated 3 immunoglobulin preparations from different pharmaceutical companies, using anti-HLA class I and II antibody specificity tests and immunocomplex capture fluorescence analysis (ICFA). RESULTS: Direct testing for anti-HLA antibodies resulted in high background errors, particularly for Venoglobulin. Diluting Venoglobulin to physiological concentrations revealed the presence of anti-HLA class I antibodies; however, no common alleles were found between the specificity identification test and ICFA.For Glovenin and Venilon, anti-HLA class I and II antibodies were detected; however, variability was observed across different test reagent lots. Moreover, dilution of the globulin formulation revealed a prozone phenomenon. CONCLUSION: The administration of IVIg complicates the accurate detection of anti-HLA antibodies, underscoring the need for careful interpretation of test results post-IVIg administration.

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[This corrects the article DOI: 10.3389/fimmu.2024.1420351.].

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BACKGROUND: COVID-19 convalescent plasma is one of the experimental therapies used widely in moderately sick COVID-19 patients. However, there are a few risks involved in plasma transfusion; notably, transfusion-related acute lung injury (TRALI) caused by antibodies against human leukocyte antigens (HLA). This study was designed to assess the prevalence of anti-HLA antibodies in convalescent plasma donors using the single antigen bead method. STUDY DESIGN AND METHODS: This was a hospital-based observational study of consecutive plasma donors. A total of 252 samples were screened for anti-HLA Class I and Class II antibodies using the microbead assay with the identification of anti-HLA Ab in positive samples being performed using a single antigen bead assay. Luminex-based normalized background cutoff ratios of 10.8 for Class I and 6.9 for Class II and mean fluorescence intensity cutoffs of 2500 for Class I and 1500 for Class II were used for screening and the single bead assay, respectively. RESULTS: Of 252 screened samples, 28 (11.1 %) were positive for Class I, Class II or both Class I and Class II anti-HLA antibodies in donors with no history of a previous immunizing event. Moreover, 20/252 (7.9%) donors without any history of prior immunization had specific anti-HLA antibodies of Class I or Class II or both by the single bead assay. CONCLUSIONS: The high prevalence of anti-HLA antibodies in our cohort of donors raises an urgent and immediate need for anti-HLA antibody screening in all convalescent plasma donors for safe therapy of COVID-19 patients.

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Background: Pre-transplant donor-specific anti-human leukocyte antigen antibody (HLA-DSA) is a recognized risk factor for acute antibody-mediated rejection (ABMR) and allograft failure. However, the clinical relevance of pre-transplant crossmatch (XM)-negative HLA-DSA remains unclear. Methods: We investigated the effect of XM-negative HLA-DSA on post-transplant clinical outcomes using data from the Korean Organ Transplantation Registry (KOTRY). This study included 2019 living donor kidney transplant recipients from 40 transplant centers in South Korea: 237 with HLA-DSA and 1782 without HLA-DSA. Results: ABMR developed more frequently in patients with HLA-DSA than in those without (5.5% vs. 1.5%, p<0.0001). Multivariable analysis identified HLA-DSA as a significant risk factor for ABMR (odds ratio = 3.912, 95% confidence interval = 1.831-8.360; p<0.0001). Furthermore, the presence of multiple HLA-DSAs, carrying both class I and II HLA-DSAs, or having strong HLA-DSA were associated with an increased incidence of ABMR. However, HLA-DSA did not affect long-term clinical outcomes, such as allograft function and allograft survival, patient survival, and infection-free survival. Conclusion: Pre-transplant XM-negative HLA-DSA increased the risk of ABMR but did not affect long-term allograft outcomes. HLA-incompatible kidney transplantation in the context of XM-negative HLA-DSA appears to be feasible with careful monitoring and ensuring appropriate management of any occurrence of ABMR. Furthermore, considering the characteristics of pre-transplant XM-negative HLA-DSA, the development of a more detailed and standardized desensitization protocol is warranted.

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Rechazo de Injerto , Antígenos HLA , Prueba de Histocompatibilidad , Isoanticuerpos , Trasplante de Riñón , Sistema de Registros , Humanos , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/inmunología , Masculino , Femenino , Antígenos HLA/inmunología , República de Corea , Persona de Mediana Edad , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Adulto , Supervivencia de Injerto/inmunología , Factores de Riesgo , Resultado del Tratamiento , Donantes de Tejidos

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BACKGROUND: BK polyomavirus (BKV) DNAemia is a challenging infectious complication after kidney transplant (KT). Reduction of immunosuppression is the mainstay of management, and tacrolimus is often the first immunosuppressive medication adjusted upon the diagnosis of BKV DNAemia. This study aimed to evaluate the impact of a new institutional protocol with lower target tacrolimus levels on BKV DNAemia, allograft rejection, and de novo donor-specific antibodies (dnDSA) among pediatric KT recipients. METHODS: We conducted a retrospective chart review of all KT episodes between January 2013 and December 2018. The new protocol with lower target tacrolimus levels was implemented in March 2015. One hundred twenty-seven patients were included in primary analysis. All patients received induction with basiliximab and methylprednisolone and were maintained on a steroid-based immunosuppressive regimen. RESULTS: In the post-intervention cohort, cumulative incidence of BKV DNAemia at 100 days (13.4% vs. 17.8%, p = .605) and 18 months post-KT (34.1% vs. 26.7%, p = .504) was not significantly different from the pre-intervention cohort. Biopsy-proven rejection rate did not change. However, we observed a trend toward earlier development of dnDSA in the post-intervention cohort using the Kaplan-Meier survival analysis (log-rank p = .06). Younger recipient age at the time of transplant was found to slightly increase the risk of BKV DNAemia (OR: 1.09, 95% CI [1.01, 1.16], p = .024). There was an association between BKV DNAemia and biopsy-proven rejection of any type (adjustedOR: 2.77, 95% CI [1.26, 6.23], p = .012), especially acute T-cell-mediated rejection grade 1A and above (adjustedOR: 2.95, 95% CI [1.06, 8.30], p = .037), after adjusted for recipient age at the time of transplant. CONCLUSIONS: Targeting lower tacrolimus levels did not decrease the incidence of BKV DNAemia within 100 days or 18 months post-KT, nor did it increase the risk of biopsy-proven rejection among pediatric KT recipients in our center. However, there was a trend toward earlier development of dnDSA, which may portend worse long-term graft outcome post-KT. Our findings highlight the need for individualized immunosuppressive regimens based on immunologic and infectious risk factors and the importance of implementing innovative biomarkers to guide therapy and improve outcomes.

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Virus BK , Rechazo de Injerto , Inmunosupresores , Trasplante de Riñón , Infecciones por Polyomavirus , Tacrolimus , Infecciones Tumorales por Virus , Humanos , Estudios Retrospectivos , Masculino , Femenino , Rechazo de Injerto/prevención & control , Rechazo de Injerto/sangre , Rechazo de Injerto/inmunología , Niño , Tacrolimus/uso terapéutico , Inmunosupresores/uso terapéutico , Infecciones por Polyomavirus/sangre , Adolescente , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/inmunología , Preescolar , ADN Viral/sangre , Lactante , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/virología

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BACKGROUND: Optimizing graft survival and diminishing human leukocyte antigen (HLA) sensitization are essential for pediatric kidney transplant recipients. More precise HLA matching predicting epitope mismatches could reduce alloreactivity. We investigated the association of predicted HLA B- and T-cell molecular mismatches with the formation of de novo donor-specific antibodies, HLA antibodies, rejection, and graft survival. METHODS: Forty-nine pediatric kidney transplant recipients transplanted from 2009 to 2020 were retrospectively studied. Donors and recipients were high-resolution HLA typed, and recipients were screened for HLA antibodies posttransplant. HLA-EMMA (HLA Epitope MisMatch Algorithm) and PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) predicted the molecular mismatches. The association of molecular mismatches and the end-points was explored with logistic regression. RESULTS: Five recipients (11%) developed de novo donor-specific antibodies. All five had de novo donor-specific antibodies against HLA class II, with four having HLA-DQ antibodies. We found no associations between PIRCHE-II or HLA-EMMA with de novo donor-specific antibodies, HLA sensitization, graft loss, or rejection. However, we did see a tendency towards an increased odds ratio in PIRCHE-II predicting de novo donor-specific antibodies formation, with an odds ratio of 1.12 (95% CI: 0.99; 1.28) on HLA class II. CONCLUSION: While the study revealed no significant associations between the number of molecular mismatches and outcomes, a notable trend was observed - indicating a reduced risk of dnDSA formation with improved molecular match. It is important to acknowledge, however, that the modest population size and limited observed outcomes preclude us from making definitive conclusions.

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Rechazo de Injerto , Supervivencia de Injerto , Antígenos HLA , Prueba de Histocompatibilidad , Trasplante de Riñón , Linfocitos T , Humanos , Rechazo de Injerto/inmunología , Niño , Supervivencia de Injerto/inmunología , Femenino , Masculino , Estudios Retrospectivos , Adolescente , Preescolar , Antígenos HLA/inmunología , Linfocitos T/inmunología , Isoanticuerpos/inmunología , Isoanticuerpos/sangre , Lactante , Antígenos HLA-B/inmunología , Linfocitos B/inmunología

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A 43-year-old woman was referred to our department for hematopoietic stem cell transplantation for acute myeloid leukemia, as she failed to achieve remission following induction therapy. Umbilical cord blood transplantation was initially planned; however, multiple anti-human leukocyte antigen (HLA) antibodies with a mean fluorescence intensity of over 10,000 were detected, and optimal umbilical cord blood could not be obtained. The plan was then switched to peripheral blood stem cell transplantation (PBSCT) from the patient's son, who had a 5/8 HLA haploidentical match. However, the patient had donor-specific antibodies against the donor's HLA-B 0702 and HLA-C 0702. To address this issue, after rituximab therapy, the patient was given platelet transfusions from B0702- and C0702-positive donors on day - 1 and day 0, and immunoglobulin on day 0, followed by PBSCT. Donor-specific antibodies decreased by over 90%, and engraftment was confirmed on day 13. Since then, the patient has remained relapse-free and healthy. This case suggests that appropriate management of donor-specific antibodies can enable safe transplantation, even in donors who test positive for these antibodies.

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Antígenos HLA , Humanos , Femenino , Adulto , Antígenos HLA/inmunología , Desensibilización Inmunológica/métodos , Donantes de Tejidos , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/inmunología , Rituximab/uso terapéutico , Rituximab/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante Haploidéntico , Isoanticuerpos/inmunología , Isoanticuerpos/sangre , Trasplante de Células Madre de Sangre Periférica , Transfusión de Plaquetas

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BACKGROUND: With the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA. RESULTS: There were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA. CONCLUSIONS: The prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

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High donor-derived cell-free DNA (dd-cfDNA) levels indicate transplant allograft injury and can identify graft rejection in kidney transplant recipients. Here, we evaluated the use of dd-cfDNA in pediatric kidney transplant rejection monitoring and treatment. METHODS: Forty-two pediatric kidney transplant patients were enrolled between February 2020 and August 2021. Dd-cfDNA was tested before and after biopsy/rejection treatment. There was a total of 61 allograft biopsies (44 for-cause, 17 surveillance). RESULTS: Graft rejection was found in 35/61 biopsies. Rejection was more common in basiliximab induction compared to rATG (77.1% vs. 22.9%, p = .0121). Median dd-cfDNA was higher in those with rejection (1.2% [0.34-3.12] vs. 0.24% [0.08-0.78], p < .0001). Dd-cfDNA was highest in biopsies with AMR and mixed AMR/TCMR. In addition, dd-cfDNA in basiliximab induction was higher compared to rATG (0.92% [0.27-1.8] vs. 0.26% [0.08-2], p = .0437). Median change in dd-cfDNA after rejection treatment was -0.57% (-1.67 to 0.05). Median time to dd-cfDNA <1% post-rejection treatment was 8.5 days (3.0-19.5). Dd-cfDNA in AMR was higher compared to TCMR or mixed rejection, and levels remained higher in AMR after treatment. In surveillance biopsies, 4/17 had rejection. Median dd-cfDNA was not different in those with versus without rejection (0.48% vs. 0.28%, p = .2342). Those without rejection all had dd-cfDNA <1%. In those with rejection, only one patient had dd-cfDNA >1%, and all had TCMR. CONCLUSIONS: Our findings support dd-cfDNA as a useful indicator of graft rejection and response to treatment. Additional studies are needed to determine the role of dd-cfDNA in graft health surveillance.

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Ácidos Nucleicos Libres de Células , Trasplante de Riñón , Humanos , Niño , Basiliximab , Donantes de Tejidos , Trasplante Homólogo , Rechazo de Injerto/etiología , Receptores de Trasplantes

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【Objective】 To explore the risk factors for the production of anti-HLA antibodies in patients with hematological diseases before hematopoietic stemcell transplantation. 【Methods】 The results and clinical data of 1 008 patients with hematological diseases in our hospital who underwent anti-HLA antibody testing were collected by using Luminex technology platform before transplantation from 2016 to 2018 for statistical analysis. 【Results】 The total positive rate of anti-HLA antibodies in 1 008 patients was 24.08%. Multivariate analysis showed that independent risk factors associated with the production of anti-HLA antibodies included age≥30 years old(P=0.046, OR1.467, 95%CI1.007-2.136), time from disease diagnosis to antibody testing≥41 days(P=0.000, OR1.830, 95%CI1.306-2.565), initial platelet count<20×109/L(P=0.020, OR1.543, 95%CI1.072-2.220), prior pregnancy(P=0.000, OR5.187, 95%CI3.689-7.293), transfusions before admission(P=0.001, OR1.762, 95%CI1.257-2.470)and total platelet transfusion volumes after admission≥30 U(P=0.000, OR2.352, 95%CI1.638-3.376). Age ≥30 years old(P=0.023, OR=1.839, 95%CI1.088-3.108)and prior pregnancy(P=0.042, OR=5.258, 95%CI1.062-26.038)are associated with the production of anti-HLA class Ⅰ and class Ⅱ antibodies, respectively. The time from disease diagnosis to antibody testing≥41 days(P=0.000, OR=2.873, 95%CI1.612-5.119), initial platelet count<20×109/L(P=0.008, OR=2.164, 95%CI1.225-3.822), prior pregnancy(P=0.002, OR=6.734, 95%CI1.993-22.751), transfusions before admission(P=0.001, OR=2.746, 95%CI1.531-4.925)and total platelet transfusion volumes after admission>30 U(P=0.006, OR=3.459, 95%CI1.416-8.451)are associated with the production of anti-HLA class Ⅰ and Ⅱ antibodies. 【Conclusion】 Older age, longer course of disease, lower PLT count, history of pregnancy and blood transfusion, and higher total amount of PLT transfusion are risk factors which affect the production of anti-HLA antibodies.Therefore, it is advisable to test for anti-HLA antibodies according to the situation before transplantation, which is of great value in guiding donor selection, monitoring antibody changes and improving transplant prognosis.

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The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

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Biomarcadores , Rechazo de Injerto , Supervivencia de Injerto , Trasplante de Hígado , Humanos , Trasplante de Hígado/efectos adversos , Rechazo de Injerto/patología , Rechazo de Injerto/etiología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Masculino , Femenino , Persona de Mediana Edad , Supervivencia de Injerto/inmunología , Estudios de Seguimiento , Biopsia , Biomarcadores/análisis , Biomarcadores/metabolismo , Pronóstico , Isoanticuerpos/inmunología , Isoanticuerpos/sangre , Fenotipo , Donantes de Tejidos , Factores de Riesgo , Adulto , Antígenos HLA/inmunología , Aloinjertos , Estudios Retrospectivos

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The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) against anti-HLA-A, -B, -C, and -DRB1 in HLA-mismatched hematopoietic stem cell transplantation (HSCT) is associated with graft failure. DSAs against HLA-A, -B, -C, and -DRB1 with a mean fluorescence intensity (MFI) of greater than > 1,000 was shown to increase the risk of graft failure in single-unit umbilical cord blood transplantation (UCBT). Nevertheless, the impact of DSAs against HLA-DP or -DQ on transplantation outcomes is not fully understood. In this report, we present a case of UCBT in a patient with myelodysplastic syndrome who was positive for DSAs against HLA-DP with MFI of 1,263 before UCBT but successfully achieved neutrophil engraftment. If HLA-DP or -DQ is mismatched in UCBT, evaluating DSAs against HLA-DP or -DQ is crucial to avoid graft failure. However, the criteria for DSAs against HLA-A, -B, -C, and -DRB1 may not be directly applicable to those against HLA-DP or -DQ.

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Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Humanos , Antígenos HLA , Antígenos HLA-DP , Síndromes Mielodisplásicos/terapia , Antígenos HLA-A

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AIMS: The presence of anti-human leucocyte antigen (HLA) antibodies has been implicated in a higher incidence of complications as well as mortality rate in heart transplantation. The aim of the study was to identify through non-invasive parameters early signs of myocardial dysfunction in the presence of anti-HLA antibodies but without evidence of antibody-mediated rejection (AMR) and its possible prognostic impact. METHODS AND RESULTS: A total of 113 heart-transplanted patients without acute cellular rejection (ACR) and AMR or cardiac allograft vasculopathy (CAV) were prospectively enrolled and divided into two groups ['HLA+' (50 patients) and 'HLA-' (63 patients)], based on the presence of anti-HLA antibodies. Each patient was followed for 2 years after the enrolment, recording episodes of AMR, ACR, CAV, and mortality. Clinical characteristics were similar between the two groups. Among laboratory data, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin values were significantly higher in the presence of anti-HLA antibodies (P < 0.001 and P = 0.003, respectively). The echocardiographic parameters that showed a statistically significant difference between the two groups were deceleration time of E wave (DecT E, P < 0.001), left ventricular global longitudinal strain (P < 0.001), tricuspid annular plane systolic excursion (P = 0.011), tricuspid S' wave (P = 0.002), and free wall right ventricular longitudinal strain (fwRVLS, P = 0.027), whereas left atrial strain did not differ significantly (P = 0.408). Univariate analysis showed that anti-HLA antibodies were associated with the development of CAV at both 1 and 2 year follow-up [odds ratio (OR) 11.90, 95% confidence interval (CI) 1.43-90.79, P = 0.022 and OR 3.37, 95% CI 1.78-9.67, P = 0.024, respectively]. Bivariate analysis demonstrated that both fwRVLS and DecT E were predictors of CAV development independently from HLA status. CONCLUSIONS: The presence of circulating anti-HLA antibodies is correlated with a mild cardiac dysfunction, even in the absence of AMR, and CAV development. Interestingly, reduced values of DecT E and fwRVLS were predictors of future development of CAV, independently from anti-HLA antibody.

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Trasplante de Corazón , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/métodos , Anticuerpos , Pronóstico , Rechazo de Injerto/diagnóstico , Ecocardiografía

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Donor-specific anti-HLA antibody (DSA) is a significant obstacle to successful haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and is associated with poor engraftment rates. DSA strongly positive patients with a mean fluorescence intensity (MFI) over 5000 have a primary poor graft function (PGF) rate of over 60%. Currently, there is no consensus on the desensitization of DSA, and existing strategies are complex and have limited effectiveness. To address this issue, we conducted a retrospective study on 19 patients with strongly positive DSA (MFI over 5000) who underwent haplo-HSCT and were treated with intravenous immunoglobulin (IVIg)-based therapy. We also included 38 baseline-matched patients with DSA-negative as controls. Our findings revealed that the cumulative incidence of engraftment, PGF, graft-versus-host disease (GVHD), virus infection, overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) in the DSA strongly positive group after desensitization were comparable to those in the DSA negative group (P > 0.05). Our multivariable analysis showed that disease remission was a protective factor against PGF (P = 0.005, OR = 0.019, 95% CI 0.001-0.312). Subgroup analysis revealed that the desensitization efficacy was equal regardless of DSA type against HLA-I or II, and MFI value over 5000 or not. In conclusion, we propose a simple and effective DSA desensitization strategy based on immunoglobulin to ensure successful engraftment and improve patient prognosis.

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Trasplante de Células Madre Hematopoyéticas , Trasplante Haploidéntico , Humanos , Estudios Retrospectivos , Donantes de Tejidos , Inmunoglobulinas Intravenosas/uso terapéutico , Suero Antilinfocítico , Antígenos HLA

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Several technical limitations of Luminex single antigen (LSA) assays have been described so far. This study focused on a reactivity pattern observed in many sera that cannot be explained by eplets described in the Epitope Registry database and sometimes appearing against a self-HLA allele or antigen. In most cases, this pattern is revealed by a discrepant result when compared with other assays (Luminex PRA, cell-binding assays such as flow cytometry cross match, LSA from another manufacturer…). We focus here on the Cw1/12/15 pattern appearing on the LABScreen class I LSA provided by One Lambda. We documented its behavior using this LSA after acid denaturation of the beads, using Lifecodes LSA from Immucor, and adsorption of sera either on spleen mononuclear cells from deceased donors or on single HLA transfected cell clones. We studied 33 sera from different patients positive for the three Cw beads, selected from our routine patients' LSA database. Nine patients had transplants from a Cw12 or Cw15 donor without any pejorative evolution of the graft, nor post-transplant MFI (mean fluorescence intensity) increase of the Cw1/12/15 beads. A significant increase of MFI was observed after acid denaturation of the LABScreen beads. All sera tested by Lifecodes LSA were negative for these Cw beads. Finally, we found no significant difference of MFI after adsorption on cells from either origin. Therefore, the Cw1/12/15 pattern appears to be a false positive reactivity of the LABScreen single antigen assay.

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Trasplante de Riñón , Humanos , Alelos , Prueba de Histocompatibilidad , Antígenos de Histocompatibilidad Clase I , Donantes de Tejidos , Antígenos HLA , Isoanticuerpos , Rechazo de Injerto

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Background: The clinical significance of low-level donor-specific anti-HLA antibody (low-DSA) remains controversial. We investigated the impact of low-DSA on posttransplant clinical outcomes in kidney transplant (KT) recipients. Methods: We retrospectively reviewed 1,027 KT recipients, namely, 629 living donor KT (LDKT) recipients and 398 deceased donor KT (DDKT) recipients, in Seoul St. Mary's Hospital (Seoul, Korea) between 2010 and 2018. Low-DSA was defined as a positive anti-HLA-DSA result in the Luminex single antigen assay (LABScreen single antigen HLA class I - combi and class II - group 1 kits; One Lambda, Canoga Park, CA, USA) but a negative result in a crossmatch test. We compared the incidence of biopsy-proven allograft rejection (BPAR), changes in allograft function, allograft survival, patient survival, and posttransplant infections between subgroups according to pretransplant low-DSA. Results: The incidence of overall BPAR and T cell-mediated rejection did not differ between the subgroups. However, antibody-mediated rejection (ABMR) developed more frequently in patients with low-DSA than in those without low-DSA in the total cohort and the LDKT and DDKT subgroups. In multivariate analysis, low-DSA was identified as a risk factor for ABMR development. Its impact was more pronounced in DDKT (odds ratio [OR]: 9.60, 95% confidence interval [CI]: 1.79-51.56) than in LDKT (OR: 3.76, 95% CI: 0.99-14.26) recipients. There were no significant differences in other outcomes according to pretransplant low-DSA. Conclusions: Pretransplant low-DSA has a significant impact on the development of ABMR, and more so in DDKT recipients than in LDKT recipients, but not on long-term outcomes.

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Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Prueba de Histocompatibilidad , Anticuerpos , Donantes de Tejidos , Rechazo de Injerto/diagnóstico , Antígenos HLA , Isoanticuerpos , Supervivencia de Injerto

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Solid-phase single antigen bead (SAB) assay for detection of anti-human leukocyte antigen (HLA) antibodies and high-resolution HLA typing have enabled tremendous progress in virtual crossmatch (VXM) technology in recent years. However, misinterpretation of the SAB assay may result in detrimental consequences after kidney transplantation. Meanwhile, epitope analysis could be an effective method to estimate immunizing eplets, which may provide ancillary information for better understanding of the SAB assay. To perform epitope analysis appropriately, it is necessary to understand the basic principles related to histocompatibility testing and the characteristics of the SAB assay. Therefore, knowledge of the properties and limitations of the SAB assay is critical. In this review, we aim to describe the fundamental concepts regarding immunobiological assessment, including HLA, anti-HLA antibodies, and SAB assay, and explain epitope analysis using examples.

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Trasplante de Riñón , Médicos , Humanos , Epítopos , Antígenos HLA , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Rechazo de Injerto/prevención & control

RESUMEN

To examine the production time, type, and MFI of post-transplantation de novo HLA antibodies, and their effects on haplo-HSCT outcomes, we retrospectively included 116 patients who were negative for pre-existing HLA antibodies. In total, 322 serum samples from pre-transplantation to post-transplantation were dynamically tested by Luminex and single-antigen bead reagents. Patients were divided into: HLA antibody persistently negative group (group 1), the de novo HLA antibody transiently positive group (group 2), the de novo HLA antibody non-persistently positive group (group 3), and the de novo HLA antibody persistently positive group (group 4). Group 4 included DSA+non-DSA (NDSA) (group 4a) and NDSA (group 4b) groups. The detection rate of de novo HLA antibodies was 75.9% (88/116). The median MFI for de novo HLA antibodies was 2439 (1033-20162). The incidence of II-IV aGvHD was higher in group 2 than in group 1 (52.6% vs 17.9%, P < 0.01); in group 4a than in group 1 (87.5% vs 17.9%, P < 0.001); and in group 4a than in group 4b (87.5% vs 40.0%, P = 0.001). The DFS (37.5% vs 85.7%, P < 0.01) and OS (37.5% vs 85.7%, P < 0.01) of group 4a were lower than those of group 1. The DFS (48.0% vs 85.7%, P < 0.01) and OS (56.0% vs 85.7%, P = 0.03) of group 4b were lower than those of group 1. Multivariate analysis showed that de novo HLA antibody being transiently positive (HR: 5.30; 95% CI: 1.71-16.42, P = 0.01) and persistently positive (HR: 5.67; 95% CI: 2.00-16.08, P < 0.01) were both associated with a higher incidence of II-IV aGvHD. Persistently positive de novo HLA antibodies were a risk factor for reduced DFS (HR: 6.57; 95% CI: 2.08-20.70, P < 0.01) and OS (HR: 5.51; 95% CI: 1.73-17.53, P < 0.01). DSA and NDSA can be detected since 15 days after haplo-HSCT in patients without pre-existing HLA antibodies, and affect aGvHD, DFS, and OS. Haplo-HSCT patients must be monitored for HLA antibodies changes for appropriate preventive clinical management, and we recommend that 1-month post-transplantation is the best test time point.

Asunto(s)

Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios Retrospectivos , Neoplasias Hematológicas/terapia , Anticuerpos , Factores de Riesgo , Trasplante de Células Madre Hematopoyéticas/efectos adversos

RESUMEN

Introduction Limited information exists concerning the clinical significance of histologically confirmed antibody-mediated rejection (h-AMR) without detectable circulating donor-specific antibodies (DSA). In this study, we compared the outcomes of patients with h-AMR according to DSA status. Methods A total of 80 kidney transplant (KT) recipients who met the 2018 Banff criteria for h-AMR were included. Clinical and immunological characteristics were evaluated, and outcomes were compared according to DSA status after kidney biopsy (KB). Results There were 57 patients who had DSA-positive (+) h-AMR and 23 patients who had DSA-negative (-) h-AMR. Groups had similar baseline characteristics and time between KT and KB. Concerning histopathological diagnoses/Banff scores, DSA+ patients had higher interstitial fibrosis (ci) and tubular atrophy (ct) (ci+ct) scores and lower arterial hyalinosis (ah) scores compared to DSA- patients. Graft survival (GS) was similar for both groups (64% versus 44% at five years and 44% versus 34% at 10 years). Multivariate analysis revealed the time of KB (less than six months after KT or more than six months after KT) to be associated with GS. A stratified analysis was conducted, targeting DSA status according to the time of biopsy. For KB performed less than six months after KT, GS was higher for DSA+ patients at 10 years (66% versus 23%). For KB performed more than six months after KT, DSA- patients had higher GS at 10 years (58% versus 9%). Conclusion Both the timing of AMR diagnosis and DSA status had an impact on AMR outcomes. For patients diagnosed with AMR more than six months after transplantation, GS was worst for those in which circulating DSA were identified. Biopsy specimens from DSA- specimens had higher ct-ci and ah scores.

RESUMEN

OBJECTIVE: Angiotensin II type-1 receptor antibodies (AT1R-Ab) and endothelin-1 type-A receptor antibodies (ETAR-Ab) are non-human leukocyte antigen (HLA) antibodies that can elicit adverse effects on kidney transplantation (KT) outcomes. We investigated the correlation between levels of AT1R-Ab and ETAR-Ab and postoperative outcomes in KT recipients. METHODS: Pre-KT and post-KT serum from 79 patients was collected. Post-KT serum was collected within 1 year after KT or simultaneously as the biopsy. Levels of AT1R-Ab and ETAR-Ab were measured using enzyme-linked immunosorbent assay kits. AT1R-Ab >17.0 U/mL and ETAR-Ab >10.0 U/mL was considered to denote positivity according to manufacturer recommendations. We measured donor-specific antibodies against human leukocyte antigens (HLA-DSA) levels using LABScreen™ single-antigen kits. RESULTS: Seventy-nine (54 men, 25 women) formed the study cohort. Seven (8.7%) patients were positive for AT1R-Ab, 25 (31.6%) patients were positive for both AT1R-Ab and ETAR-Ab, and 47 (59.5%) were negative for both antibodies at all time points. No patients died during the study period. Patients with both AT1R-Ab and ETAR-Ab were associated with a higher prevalence of antibody-mediated rejection (AMR) and lower estimated glomerular filtration rate, but not allograft loss or delayed graft function. AT1R-Ab were associated with T-cell-mediated rejection, but the association was not significant. HLA-DSA were associated significantly with a higher creatinine level in serum at 12 months and 24 months in patients with AT1R-Ab and/or ETAR-Ab. CONCLUSIONS: AT1R-Ab, ETAR-Ab, and HLA-DSA were associated with a higher prevalence of AMR and decline in graft function. Measurement of levels of AT1R-Ab and ETAR-Ab in KT patients may be useful for stratification of immunological risk and identification of patients at a high risk of adverse graft outcome.

Asunto(s)

Trasplante de Riñón , Angiotensina II , Anticuerpos , Endotelina-1 , Femenino , Rechazo de Injerto , Antígenos HLA , Humanos , Riñón/patología , Trasplante de Riñón/efectos adversos , Receptor de Angiotensina Tipo 1 , Receptor de Endotelina A