Pre-existing HLA Research Articles

Sensitive HLA antibody testing and the risk of antibody-mediated rejection and graft failure.

Solid phase detection and identification of HLA antibodies in kidney transplantation currently relies on single antigen bead (Luminex®) assays, which is more sensitive than the previously used enzyme-linked immunosorbent assays (ELISA). To evaluate the impact of more sensitive HLA testing on antibody-mediated rejection (AMR) occurrence and allograft survival, we analysed 1818 renal allograft recipients transplanted between March 2004 and May 2021. In 2008, solid phase testing switched from ELISA to Luminex. We included 393 (21.6%) transplantations before and 1425 (78.4%) transplantations after transition from ELISA- to Luminex-based testing. For this study, bio-banked ELISA era samples were tested retrospectively with Luminex. Significantly less pretransplant DSA were found in patients transplanted with pre-existing HLA antibodies in the Luminex (109/387) versus the ELISA period (43/90) (28% vs. 48%, p < 0.01). Throughout histological follow-up, 169 of 1818 (9.3%) patients developed AMR. After implementing Luminex-based testing, the rate of AMR significantly decreased (p = 0.003). However, incidence of graft failure did not significantly differ between both eras. In conclusion, less patients with pretransplant DSA were transplanted since the implementation of Luminex HLA testing. Transition from ELISA- to Luminex-based HLA testing was associated with a significant decrease in AMR occurrence post-transplantation. Since the decline of AMR did not translate into improved graft survival, Luminex-based testing has the added value of preventing low-risk AMR cases. Therefore, Luminex' high sensitivity must be balanced against waiting time for a suitable organ.

Haemophagocytic Lymphohistiocytosis Following the anti-PD-1 Nivolumab in a Patient with Gastric Cancer and Ankylosing Spondylitis.

Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs. We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed. In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs. Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.

Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) Tcells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of isletallo-transplantation. We find that treatment of allo-sensitized hosts with CAR Tcells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent isletallografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.

Posttransplant de novo DSA and NDSA affect GvHD, OS, and DFS after haplo-HSCT in patients without pre-existing HLA antibodies of hematological malignancies.

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.

P16.07: Association Between SARS-CoV-2 Infection and de Novo HLA Donor Specific Antibody Production in Lung Transplant Recipients: Single-Center Study

Introduction: COVID-19 pandemic has led to significant morbidity and mortality in lung transplant recipients. Respiratory viral infections may be associated with de-novo HLA donor-specific antibody production and impacting lung transplant outcome. Methods: Since one of the immunomodulation strategies post-SARS-CoV-2 infection in lung transplant recipients include decreasing or holding anti-metabolites, concerns have been raised for higher incidence of de-novo HLA donor specific antibody production in lung transplant recipients. We performed a retrospective chart review of 24 consecutive lung transplant recipients diagnosed with COVID-19 to investigate this concern. Results: We observed no significant association between SARS-CoV-2 infection and immunomodulation on pre-existing or de novo HLA donor specific antibodies. Conclusion: SARS-CoV-2 infection was not associated with a significant increase in de-novo HLA DSA production or MFI levels of pre-existing HLA DSA compared to pre-COVID-19 diagnosis in lung transplant recipients. These results provide a valuable insight on the effects of SARS-CoV-2 infection on immunogenicity in lung transplant recipients.

From bench to bedside: reversing established antibody responses and desensitization.

Basic transplant immunology has primarily focused on the definition of mechanisms, but an often-stated aspirational goal is to translate basic mechanistic research into future therapy. Pretransplant donor-specific antibodies (DSA) mediate hyperacute as well as early antibody-mediated rejection (AMR), whereas DSA developing late posttransplantation may additionally mediate chronic rejection. Although contemporary immunosuppression effectively prevents early cellular rejection after transplant in nonsensitized patients, it is less effective at controlling preexisting HLA antibody responses or reversing DSA once established, thus underscoring a need for better therapies. We here review the development of a bench-to-bedside approach involving transient proteasome inhibition to deplete plasma cells, combined with maintenance co-stimulation blockade, with CTLA-4Ig or belatacept, to prevent the generation of new antibody-secreting cells (ASCs). This review discusses how this treatment regimen, which was rationally designed and validated to reverse established DSA responses in mouse models, translated into reversing active AMR in the clinic, as well as desensitizing highly sensitized patients on the transplant waitlist.

COVID-19 does not impact HLA antibody profile in a series of waitlisted renal transplant candidates

HLA antibodies are typically produced after exposure to transplanted tissue, pregnancy, and blood products. Sensitization delays access to transplantation and preclude utilization of donor organs. Infections and vaccinations have also been reported to result in HLA antibody formation. It is not known if patients develop HLA antibodies after infection with SARS-CoV-2. Here we analyzed a series of eighteen patients waiting for kidney transplantation who had symptomatic COVID-19 disease and recovered. None of the patients in this initial series developed de novo HLA antibodies. Notably, there was no increase in preexisting HLA antibodies in four highly sensitized patients with a CPRA > 80%. These preliminary data suggest that there may not be a need to repeat HLA antibody testing or perform a physical crossmatch on admission serum before kidney transplant for COVID-19 recovered patients. Data from a large number of patients with different demographics needed.

The impact of pre-existing HLA and red blood cell antibodies on transfusion support and engraftment in sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation from HLA-matched sibling donors: A prospective, single-center, observational study.

BackgroundHematopoietic stem cell transplantation (HSCT) is curative for patients with sickle cell disease (SCD). Prior to HSCT, patients with SCD commonly receive RBC transfusions with some becoming RBC or HLA alloimmunized. This alloimmunization may impact post-HSCT transfusion requirements and donor engraftment.MethodsThe study population included patients with SCD transplanted on a single-center nonmyeloablative, HLA-matched sibling HSCT trial at the National Heart, Lung, and Blood Institute (NHLBI) who had a pre-HSCT sample available for HLA class I antibody testing. We evaluated transfusion requirements and engraftment outcomes comparing patients with and without pre-existing HLA and RBC antibodies.FindingsOf 36 patients studied, 10 (28%) had HLA class I antibodies and 11 (31%) had a history of RBC alloantibodies. Up to day +45 post-HSCT, patients with HLA antibodies received more platelet transfusions (median 2.5 vs 1, p = 0.042) and those with RBC alloantibodies received more RBC units (median 7 vs 4, p = 0.0059) compared to respective non-alloimmunized patients. HLA alloimmunization was not associated with neutrophil engraftment, donor chimerism, or graft rejection. However, RBC alloimmunization correlated with a decreased donor T cell chimerism at 1 year (median 24% vs 55%, p = 0.035).InterpretationPre-existing HLA and RBC alloantibodies are clinically significant for patients undergoing HLA-matched nonmyeloablative HSCT. Testing for both HLA and RBC antibodies is important to help estimate transfusion needs peri‑HSCT. The association of lower donor T cell chimerism and pre-existing RBC alloantibodies needs further investigation.FundingNIH Clinical Center and NHLBI Intramural Research Program (Z99 CL999999, HL006007–11) and the Thrasher Research Fund.

Pre-Formed Donor-Specific Antibodies Impact Long Term Survival of Heart Transplants

We previously reported that heart transplant (HTx) recipients with pre-formed, anti-HLA antibodies at low titer had one-year survival that was comparable to patients without any anti-HLA antibodies. As a result, we defined unacceptable HLA antigens by MFI>1000 in serum at 1:16 dilution. The current study evaluates how pre-formed, low-titer, donor-specific antibodies (DSA) and positive crossmatch affect long term survival of HTx recipients. Total 495 adult recipients transplanted at our center between Jan. 2007 and Dec. 2016 were studied. Prior to HTx, recipients had HLA antibody screening (FlowPRA) and specificity testing (LABScreen). Unacceptable HLA antigens were defined by MFI>1000 in serum at 1:16 dilution. Acceptable donors were selected by virtual crossmatch using the criteria above, and flow cytometry crossmatch (FCXM) was performed peri- or post-HTx. Recipients transplanted across low titer DSA, positive in undiluted serum but negative at 1:16 dilution, received peri-operative plasmapheresis. We used log-rank testing to evaluate survival in the following groups compared to their controls: (1) presence of any pre-formed HLA antibodies; (2) presence of pre-formed DSA; and (3) positive FCXM. Of 495 HTx recipients, 179 (36%) had pre-existing HLA antibodies, and their overall survival was not different from patients without HLA antibodies (p=0.883). However, median survival time was reduced in patients with pre-formed DSA (n=62), compared to DSA-negative recipients (n=117): 9.1 years (95% CI 3.52 to 14.65) vs. 10.9 years (95% CI 6.13 to 15.70); p=0.02. The survival rates for 1-, 3-, 5-year of DSA-negative recipients were 91.5%, 85.4% and 79.5%, and the DSA-positive recipients were 83.9%, 66.1% and 61.7%, respectively. Total 62 recipients had pre-HTx DSA. Among them, 26 had a positive FCXM (46%). The survival rates of FCXM-positive cases were lower than FCXM-negative cases (n=36) at 1, 3, and 5 years: 80.8%, 57.9%, 52.1% vs. 86.1%, 71.4%, 67.6%. Our findings suggest that pre-formed DSA, even at low titer, negatively impacted HTx survival. Cases with positive FXCM had the worst outcomes. Avoiding all pre-formed DSA may improve survival for HTx patients, but may increase waitlist mortality. To improve the HTx survival, close post-transplant monitoring and proactive immunological management may be required when pre-formed DSA are present.

Distinct Evolutionary Patterns in Chronic Lymphocytic Leukemia (CLL) during Resistance to Graft-Versus-Leukemia (GvL)

Distinct Evolutionary Patterns in Chronic Lymphocytic Leukemia (CLL) during Resistance to Graft-Versus-Leukemia (GvL)

Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term.

Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next generation CD28 blockers to prevent and reduce alloantibodies over the long-term.

Presence of Pre-Existing HLA Antibodies in Renal Transplant Patients and its Impact During the First Year Post Transplant

Presence of Pre-Existing HLA Antibodies in Renal Transplant Patients and its Impact During the First Year Post Transplant

The effect of pre-existing HLA sensitization on the renal allograft function according to angionephroscintigraphy results

An important role in assessing the transplanted kidney function recovery and diagnosing posttransplant complications belongs to angionephroscintigraphy allowing a qualitative and quantitative assessment of renal perfusion, filtration, and excretion. The aim of the study was to evaluate and monitor the allograft function after cadaveric kidney transplantation by using angionephroscintigraphy with 99mTc-Pentatech and studying the obtained results in relation to pre-existing HLA sensitization. We analyzed the results of radionuclide tests of 55 patients in the early postoperative period in time from 5 days to 3 months after transplantation. In most patients, the higher was the blood anti-HLA antibody levels in the recipient before the kidney transplantation, the more pronounced decrease in the function was noted in them according to angionephroscintigraphy results. In the treatment of patients with a primary allograft function, the function of the transplanted kidney had gradually improved by the 3–4th week, reaching normal values in a number of parameters. In patients with a delayed allograft function, only partial recovery of function was observed after 3–4 weeks. In that case, when a high level of preexisting anti-HLA antibodies had been noted, an abrupt decline in perfusion typical for an acute rejection crisis, and the filtration impairment were seen, often there was an impaired excretion, indicating a concomitant severe ischemic injury of the kidney or acute tubular necrosis. Thus, angionephroscintigraphy enables to assess the recovery of the graft function thanks to a separate evaluation of the function components, and in combination with the test for preexisting anti-HLA antibodies, helps to make a differential diagnosis of an acute rejection crisis and acute tubular necrosis allowing the choice of an adequate treatment tactics.

Effects of preexisting donor-specific HLA antibodies for graft failure in un-manipulated haploidentical hematopoietic stem cell transplantation

目的探讨单倍体相合造血干细胞移植中HLA供者特异性抗体（DSA）对干细胞植入的影响以及处理方法。方法采用免疫磁珠液相芯片技术，对2016年6月至2017年5月拟行单倍体相合造血干细胞移植患者进行HLA抗体及DSA的检测，对已完成移植患者进行DSA与植入失败相关性分析，检测移植前后DSA水平，探索针对DSA的处理方法。结果共检测了92例拟行单倍体相合造血干细胞移植患者的HLA抗体，其中16例（17.4%）存在HLA抗体，6例（6.5%）DSA阳性。在常规清髓性预处理单倍体相合移植中，26例DSA阴性患者中有24例成功植入，仅有2例发生植入失败，而采用常规预处理的4例DSA阳性患者中仅有1例成功植入，其余3例发生植入失败，二组患者植入率差异有统计学意义[92.3%（24/26）对25.0%（1/4），χ2=8.433，P=0.004]。多因素分析显示，DSA是影响供者干细胞植入的唯一因素[OR=12.0（95% CI 1.39~103.5），P=0.024]。6例DSA阳性的患者中，4例次在移植时采取了针对DSA的措施，均获得供者干细胞顺利植入，其中3例HLA-Ⅰ类DSA阳性患者（首次移植2例、二次移植1例）在输入供者干细胞之前输入供者血小板，另1例HLA-Ⅰ、HLA-Ⅱ类DSA并存患者在二次移植时更换供者并给予全身放疗、利妥昔单抗及供者血小板输注。结论DSA是导致单倍体相合造血干细胞植入失败的关键因素，移植前应进行常规检查，DSA阳性患者应选用DSA阴性供者；无合适供者时，应采取适当措施降低DSA水平以促进干细胞植入。

OR26 Taking the hla-specific memory b cell elispot to the next level: assaying the full donor hla repertoire

Aim Pre-existing or de-novo donor-specific HLA antibodies (DSA) represent an important risk factor affecting transplant outcome. Patients with a history of immunization but lacking serum DSA may harbor dormant memory B cells which can rapidly produce DSA upon re-encounter with the same HLA. Current methods to detect memory B cells mainly utilize synthetic monomeric/tetrameric HLA molecules which generally do not represent the complete HLA repertoire of an individual. Here, we present a donor-specific HLA-ELISPOT assay enabling the screening for HLA-specific memory B cells in peripheral blood of immunized individuals using cell lysates as a natural source of both HLA class I and II. Methods Peripheral blood mononuclear cells (PBMC) or splenocytes were treated with non-ionic detergents to obtain HLA-containing lysates. Human B cell hybridomas producing specific HLA antibodies were tested against these lysates for validation purposes (n = 10). Next, polyclonally activated peripheral blood B cells from women with a history of pregnancy were tested for the presence of HLA-specific memory B cells against paternal PBMC lysates as the source of HLA (n = 22). Autologous lysates served as negative controls. Results For all hybridomas tested, we detected spot formation against the lysates that contain the corresponding HLA specificities whereas no spots were observed against lysates with irrelevant HLA, indicating the specificity of the assay. Comparable number of spots in total IgG and HLA-ELISPOT assays assured that all antibody-secreting cells were detected. In women with a history of pregnancy, we found a median of 14 (range: 0–802 spots) and 9 spots (range: 0–764) per million IgG producing cells for class I and II, respectively. Conclusion This novel lysate-based ELISPOT assay allows for the first time to quantify all donor HLA class I and II-specific memory B cells and may predict anamnestic responses in transplant recipients with a history of immunization.

Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

New strategies in living donor kidney transplantation – blood group incompatible and crossover transplantation

About 40 % of all kidney transplantations in Switzerland are from living donors. The probability of blood group incompatibility between donor and recipient is 30 %. About 10 % of recipients have preexisting HLA antibodies against their potential donors. Both risks impeded transplantation until recently. Nowadays successful protocols for blood group incompatible kidney transplantation and the possibility of crossover transplantation are available and help to overcome these risks.

Transplantation: CNIs to mTOR inhibitors--effects on allosensitization?

Pre-existing HLA antibodies negatively impact long-term graft survival and might be a major risk factor for the formation of new HLA antibodies. Whether conversion of transplant recipients from calcineurin inhibitors to mammalian target of rapamycin inhibitors increases the risk of allosensitization remains to be determined.

Pretransplant donor-specific anti-HLA antibodies as predictors of early allograft rejection in ABO-compatible liver transplantation

The significance of preexisting donor-specific HLA antibodies (HLA-DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA-DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA-DSAs and class II HLA-DSAs were determined by single-antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin-eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA-DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P < 0.01) and class II (hazard ratio = 6.0, P < 0.01). Pretransplant HLA-DSAs were associated with an increased risk of ACR: P < 0.01 for class I (42% versus 18%), P < 0.001 for class II (37% versus 7%), and P < 0.001 for either class I or II (36% versus 3%). Class I or II HLA-DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA-DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single-center subjects. In conclusion, the present study indicates that pretransplant HLA-DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti-human leukocyte antigen antibodies could serve as donor-specific markers of immunoreactivity to the liver graft.

Successful lung transplantation in the presence of pre-existing donor-specific cytotoxic HLA Class II antibodies

Pre-existing HLA antibodies are a well-established causal factor for rejection and graft dysfunction after solid-organ transplantation. In lung transplant recipients, the significance of HLA antibodies has not been fully established. Although rare, several cases of hyperacute rejection of the lung allograft due to pre-existing donor-specific HLA antibodies have been described. In contrast, we describe successful lung transplantation in a patient with pre-existing donor-specific HLA antibodies. Routine screening prior to lung transplantation revealed cytotoxic HLA Class II antibodies, directed against the alpha chain of HLA-DQ, induced by a previous liver transplant. Due to clinical deterioration, it was decided to accept a lung offer without virtual crossmatching for DQ compatibility. Cytotoxic antibodies against the lung donor were confirmed retrospectively, resulting in strong positive B-cell crossmatches. Interestingly, the patient showed no clinical or histologic signs of rejection. This case demonstrates that the presence of high levels of pre-existing donor-specific HLA antibodies does not necessarily lead to rejection and graft failure. Although screening for antibodies prior to transplantation remains crucial, this study shows that we are thus far not able to predict the effect of pre-existing HLA Class II antibodies on allograft survival in individual patients.