Acute Antibody-mediated Rejection Research Articles

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

Evaluation and management of abnormal liver enzymes in the liver transplant recipient: When, why, and what now?

MHC Class I Masking to Prevent AMR in a Porcine Kidney Transplantation Model in Alloimmunized Recipients.

Through the in vitro calcein-release assay and flow cytometry, we evaluated the protective effect of a monoclonal anti-swine leukocyte antigen class I antibody (clone JM1E3) against alloreactive IgG complement-dependent cytotoxicity toward donor endothelial cells. Kidneys perfused ex vivo with JM1E3 during hypothermic machine perfusion were transplanted to alloimmunized recipients. In vitro incubation of endothelial cells with JM1E3 decreased alloreactive IgG cytotoxicity (mean complement-dependent cytotoxicity index [% of control condition] with 1 µg/mL 74.13% ± 35.26 [calcein assay] and 66.88% ± 33.46 [cytometry]), with high interindividual variability. After transplantation, acute AMR occurred in all recipients on day 1, with signs of complement activation (C5b-9 staining) as soon as 1 h after transplantation, despite effective JM1E3 binding on graft endothelium. Despite a partial protective effect of swine leukocyte antigen I masking with JM1E3 in vitro, ex vivo perfusion of the kidney with JM1E3 before transplantation was not sufficient alone at preventing or delaying AMR in highly sensitized recipients.

Morphologic and immunophenotypic evaluation of liver allograft biopsies with contemporaneous serum DSA measurements.

Acute antibody mediated rejection is increasingly identified in liver allografts as a unique form of alloimmune injury associated with donor specific antibodies (DSA). This manifests pathologically as microvascular injury and C4d uptake. Despite the liver allograft's relative resistance to alloimmune injury, liver allografts are not impervious to cellular and antibody-mediated rejection. In this blinded control study, we evaluated CD163 immunohistochemistry and applied the Banff 2016 criteria for diagnosis of acute AMR on a group of indication allograft liver biopsies from DSA positive patients and compared them to indication biopsies from DSA negative controls. Most DSA positive patients were females (75%, p=.027), and underwent transplantation for HCV infection. Significant histopathological predictors of serum DSA positivity were Banff H-score (p=.01), moderate to severe cholestasis (p=.03), and CD163 score>2 (p=.029). Other morphologic features that showed a trend with DSA positivity include Banff portal C4d-score (p=.06), bile ductular reaction (p=.07), and central perivenulitis (p=.07). The odds of DSA sMFI ≥5000 was 12.5 times higher in those with a C4d score>1 than those with aC4d score≤1 (p=.04). Incidence of definite for aAMR in the DSA positive cohort was 25% (n=5), and 0% in the DSA negative cohort. A group of 5 DSA positive cases were not classifiable by the current scheme. Sinusoidal CD163, Banff H-score, and diffuse C4d are predictors of serum DSA, and facilitate recognition of histopathological features associated with serum DSA and tissue-antibody interaction.

Efficacy of Double Membrane Filtration Immunoadsorption in Severe C1q-Binding Donor-Specific Antibody-Positive Acute Humoral Kidney Allograft Rejection: A Case Series

Introduction: Acute antibody-mediated rejection (ABMR) is an important threat to renal allograft survival in the early transplant period and the major single cause of graft loss in the first postoperative year. Semi-selective immunoadsorption (IA) remains one of the commonly applied treatments in ABMR, reducing allo-reactive antibody load. Adding double filtration plasmapheresis (DFPP) to IA might enhance therapeutic efficacy by also addressing innate humoral effectors like complement factors. Methods: Four patients with ABMR were treated with DFPP + IA. Clinical, histological, and immunological data and adverse events were retrospectively collected. Results: Here we present four high-risk treatment-refractory ABMR cases with C1q-binding donor-specific antibodies and histology of humoral rejection under treatment with DFPP + IA. While the earlier cases (within the first year after transplantation) showed marked reduction in ABMR severity and improvement of kidney function, the later cases did not respond accordingly. Late ABMR patient 1 stabilized, whereas late ABMR patient 2 did not respond to treatment. Conclusions: Our data support the consideration of DFPP + IA as a rescue treatment option in early, severe, high-risk ABMR cases in which other treatments failed.

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

401 Successful Treatment of Thrombotic Microangiopathy Due to Acute Antibody Mediated Rejection of Kidney Transplant

European multicenter study on the real-world use and clinical impact of extracorporeal photopheresis after heart transplantation

Aim of this study was to describe the real-world use of extracorporeal photopheresis (ECP) and assess its impact on clinical outcomes in the modern era of heart transplantation. Seven transplant centers from 5 European countries participated in this retrospective, observational, single-arm chart review study. All patients received ECP after heart transplantation in 2015 or later. Data were extracted from medical records between November 2020 and December 2021. Overall, 105 patients were enrolled and followed for an average of 2 years after initiation of ECP. Reasons to start ECP were acute cellular rejection (35.2%), rejection prevention (32.4%), mixed rejection (18.1%), and antibody-mediated rejection (14.3%). Rejection ISHLT grades improved from start to end of ECP treatment in 92% of patients treated with ECP for rejection. Of patients who started ECP to prevent rejection, 88% remained free from any rejection despite a reduction of calcineurin inhibitors. Overall survival was 95%, and no deaths were related to ECP. Safety events occurred in 18 patients, of which 13 experienced complications with venous access. This study, the largest European ECP study in heart transplantation, demonstrates that ECP can effectively be used to treat different rejection types and to prevent rejection in the modern era of immunosuppression. Patients with rejections who have received ECP have shown high response as measured by histological improvements in ISHLT classification. A high percentage of patients in the prevention group remained free from rejection despite reduction in immunosuppression, in particular calcineurin inhibitors.

Association Between De Novo C1q-Binding Donor-Specific Anti-HLA Antibodies and Clinical Outcomes After Kidney Transplantation: A Meta-Analysis

Donor-specific antibodies (DSAs) are recognized as an important factor of kidney allograft loss as a subsequent event of antibody-mediated rejection (AMR). The clinical relevance of de novo DSAs (dnDSAs) after kidney transplant, particularly in their ability to bind C1q, has been widely investigated to various extents among studies. A recent study was performed to examine the association between C1q-binding dnDSAs and succeeding clinical events after kidney transplant. A meta-analysis of studies published before April 2021 was conducted from PubMed, Science Direct, and Cochrane databases. Publications on dnDSA after kidney transplant focusing on differentiation between C1q-binding and non-C1q-binding were included. The outcomes analyzed were AMR rate and allograft loss. Studies using preformed DSA were excluded. The pooled risk ratio and 95% confidence interval (CI) were analyzed using Mantzel-Haenzel method, and the I2 value was used to determine the heterogeneity of the studies. Data analysis was conducted using Review Manager 5.3. A total of 535 patients from 13 studies who developed dnDSA after kidney transplant were analyzed. Among these, 239 (44.7%) had C1q-binding and 296 (55.3%) had non-C1q-binding dnDSA. Acute AMR was found in 59.2% (97/164) of the C1q-binding group and in 28.8% (49/170) of the non-C1q-binding group (risk ratio [RR], 0.58 [95% CI, 0.39-0.85], P = .006, I2=58%). Chronic AMR was found in 50% (19/38) of the C1q-binding group and in 16.9% (11/65) of the non-C1q-binding group (RR, 0.39 [95% CI, 0.21-0.71], P=.002, I2=0%). Allograft loss was found in 62.2% (74/119) of the C1q-binding group and in 34.1% (60/176) of the non-C1q-binding group (RR, 0.57 [95% CI, 0.38-0.85], P = .006, I2=61%). This meta-analysis demonstrates that patients who developed C1q-binding dnDSA display an increased risk of AMR and allograft loss compared with those with non-C1q-binding dnDSA. Therefore, C1q-binding dnDSAs are associated with inferior outcomes after kidney transplant.

Pre-existing non-human leukocyte antigen antibodies are associated with allograft rejection after thoracic transplantation

BackgroundThere is growing evidence on the important role of non-human leukocyte antigen (HLA) antibodies in lung and heart transplant rejection. Since data on the prevalence and clinical significance of non-HLA antibodies in the Asian population are scarce, we analyzed non-HLA antibodies in heart and lung transplant patients. MethodsWe used the Luminex method to measure non-HLA antibodies in patients who underwent heart transplantation (N = 28) or lung transplantation (N = 36) between 2016 and 2019. We evaluated the association between pre-existing non-HLA antibodies and acute rejection-free days in these recipients. ResultsOf 64 patients, 27 (42.2%) patients underwent rejection, with 26 (40.6%) acute cellular rejection and one (1.6%) acute antibody-mediated rejection. Among 33 identified different non-HLA antibodies, only the anti-glutathione S-transferase theta-1 (GSTT1) antibody positive rate was significantly higher in patients with acute rejection compared to those without rejection (14.8% vs. 0%, p = 0.016). The angiotensin II type I receptor positive rate was not significantly different between the two groups (40% vs. 18.5%, p = 0.129). In the multivariate Cox regression analysis, anti-GSTT1 antibody-positive patients had a higher risk of acute allograft rejection (hazard ratio, 4.19; 95% confidence interval [CI], 1.41–12.49; p = 0.010). The Kaplan-Meier curve showed that anti-GSTT1 antibody-positive patients had fewer acute rejection-free days (χ2 = 7.892; p = 0.005). Additionally, patients who underwent platelet transfusion (odds ratio, 1.49; 95% CI, 1.16–1.91; p = 0.002) before transplantation were more likely to be positive for anti-GSTT1 antibody. ConclusionPatients with antibodies against GSTT1 before heart or lung transplantation have anincreased risk of acute rejection.

Optimal dose of rituximab in ABO-incompatible kidney transplantation in patients with low anti-A/B antibody titers: A single-center retrospective cohort study.

The clinical outcomes of ABO-incompatible (ABOi) kidney transplantation have improved with the introduction of desensitization therapy with rituximab. However, rituximab prevents not only antibody-mediated rejection (AMR) but also increases the risk of adverse events, such as infection. For ABOi kidney transplantation in patients with low anti-A/B antibody titers, we previously used a rituximab-free desensitization protocol and then initiated a single dose of 100mg rituximab in 2016. We retrospectively compared the outcomes of ABOi kidney transplantation in patients with low anti-A/B antibody titers before and after the introduction of rituximab. ABOi kidney transplantations (n=142) in patients with low anti-A/B antibody titers between 2007 and 2021 were included. Patients were divided into two groups (with and without rituximab) for desensitization. The primary outcomes were the incidence of acute AMR and infection. Sixty-six patients were desensitized without rituximab (rituximab-free group), and 76 were pretreated with 100mg rituximab (rituximab group) before transplantation. The incidence of acute AMR was significantly lower in the rituximab group than in the rituximab-free group (.0% [0/76] vs. 7.6% [5/66], respectively; p=.047). Post-transplantation anti-A/B antibody titers were also lower in the rituximab group than in the rituximab-free group. There was no significant difference in the incidence of adverse events, including infections, between the two groups. In ABOi kidney transplantation patients with low anti-A/B antibody titers, the desensitization protocol with a single dose of 100mg rituximab was effective in preventing acute AMR without increasing the risk of other adverse events.

Comparative Analysis of Determinants and Outcome of Early and Late Acute Antibody Mediated Rejection (ABMR).

Antibody-mediated rejection (ABMR) is one of the major determinants of graft survival. Although diagnostic precision and treatment options have improved, response to therapy and graft survival has not improved very significantly. The phenotypes of early and late acute ABMR differ in many ways. In this study, we assessed the clinical characteristics, response to therapy, DSA positivity, and outcomes of early and late ABMR. During the study period, 69 patients with acute ABMR diagnosed on renal graft histopathology were included with a median follow-up of 10 months after rejection. Recipients were stratified into early acute ABMR (<3 months of transplant; n = 29) and late acute ABMR (>3 months of transplant; n = 40). Graft survival, patient survival, response to therapy, and doubling of serum creatinine were assessed and compared between the two groups. Baseline characteristics and immunosuppression protocols were comparable between the early and late ABMR groups. Late acute ABMR had an increased risk of doubling of serum creatinine than the early ABMR group (P = 0.002). Graft and patient survival were not statistically different between the two groups. Response to therapy was inferior in the late acute ABMR group (P = 0.00). Pretransplant DSA was present in 27.6% in the early ABMR group. Late acute ABMR was frequently associated with nonadherence or suboptimal immunosuppression and low DSA positivity (15%). Infections such as CMV, bacterial, and fungal infections were similar in the earlier and late ABMR groups. Late acute ABMR group had a poor response to anti-rejection therapy and also an increased risk of doubling of serum creatinine compared to the early acute ABMR group. There was also a tendency toward increased graft loss in late acute ABMR patients. Late acute ABMR patients are more frequently associated with nonadherence/suboptimal immunosuppression. There was also a low incidence of anti-HLA DSA positivity in late ABMR.

Coexistent De novo membranous and collapsing glomerulopathies in the allograft: Unusual alloimmune injury

We describe a kidney transplant recipient who presented 7 months after transplantation with nephrotic proteinuria and graft dysfunction, which on biopsy revealed two concomitant lesions: de novo membranous and collapsing glomerulopathies. While the index episode responded favorably to plasmapheresis and rituximab, repeat evaluation 4 months later showed an evolution of acute antibody-mediated rejection, along with the remnant pathologies.

Liver Transplantation from a Human Leukocyte Antigen-Matched Sibling Donor: Effectiveness of Direct-Acting Antiviral Therapy against Hepatitis C Virus Infection

Through living-donor liver transplantation (LDLT) from a human leukocyte antigen (HLA)-matched sibling donor, it may be possible to stop the use of immunosuppressants. It is possible that acute antibody-mediated rejection and chronic active antibody-mediated rejection through the positivity of donor-specific anti-HLA antibodies and/or T cell-mediated rejection may affect the prognosis of liver transplantation. The etiologies of liver diseases of the recipient may also affect the post-transplantation course. Herein, we report on the successful re-treatment with direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection in a patient who underwent a LDLT from HLA-matched sibling donor. After liver transplantation for HCV-related liver diseases, it is easy for HCV to re-infect the graft liver under a lack of immunosuppressants. DAA therapy against HCV re-infection immediately after transplantation should be commenced, and it is important to eradicate HCV for better prognosis of the recipients in LDLT for HCV-related liver diseases.

Long-term follow-up of acute and chronic rejection in heart transplant recipients from hepatitis C viremic (NAT+) donors

The long-term safety of heart transplants from hepatitis C viremic (NAT+) donors remains uncertain. We conducted a prospective study of all patients who underwent heart transplantation at our center from January 2018 through August 2020. Routine testing was performed to assess for donor-derived cell-free DNA, acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV). Allograft dysfunction and mortality were also monitored. Seventy-five NAT- recipients and 32 NAT+ recipients were enrolled in the study. All NAT+ recipients developed viremia detected by PCR, were treated with glecaprevir/pibrentasvir at the time of viremia detection, and cleared the virus by 59 days post-transplant. Patients who underwent NAT testing starting on post-operative day 7 (NAT+ Group 1) had significantly higher viral loads and were viremic for a longer period compared with patients tested on post-operative day 1 (NAT+ Group 2). Through 3.5 years of follow-up, there were no statistically significant differences in timing, severity, or frequency of ACR in NAT+ recipients compared with the NAT- cohort, nor were there differences in noninvasive measures of graft injury, incidence or severity of CAV, graft dysfunction, or mortality. There were five episodes of AMR, all in the NAT- group. There were no statistically significant differences between Group 1 and Group 2 NAT+ cohorts. Overall, these findings underscore the safety of heart transplantation from NAT+ donors.

Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion.

Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation. Discarded human kidneys with wide ranging demographics and cold ischaemia times (11-54h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600μg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1+2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition. Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition. We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR. The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.

Low Incidence of Acute Antibody-Mediated Rejection after HLA Desensitization in Living Donor Kidney Transplant Recipients.

Desensitization allows the performance of human leukocyte antigen (HLA)-incompatible transplants. However, the incidence of acute rejection (AR) is high. This study aims to analyze the incidence of AR after transplantation with HLA-incompatible living donors in patients who underwent desensitization. Patients were immunosuppressed with tacrolimus, mycophenolic acid derivatives, and steroids after being desensitized with rituximab, plasma exchange, and/or immunoadsorption with specific cytomegalovirus immunoglobulins. A negative complement-dependent cytotoxicity or flow cytometry crossmatch and a donor-specific antibody titer < 1000 mean fluorescence intensity (MFI) were used to determine desensitization efficacy. A total of 36 patients underwent desensitization, and 27 (75%) were transplanted. After a follow-up of 58 ± 58 months (Min−Max: 0.13−169.5), five episodes of AR occurred: two antibody-mediated and three T-cell-mediated. No differences were found in baseline calculated panel-reactive antibodies (cPRA), class I or II MFI, number of antibodies, or Relative Intensity Scale (RIS) between AR and non-AR patients. Patients with antibody-mediated AR had higher cPRA (NS), MFI class I (p = 0.07) and class II (p = 0.006), and RIS (p = 0.01). The two patients with antibody-mediated AR and one patient with T-cell-mediated AR lost their grafts. In conclusion, the incidence of acute antibody-mediated rejection after desensitization was 7.4%, which occurred early post-transplantation in patients with high MFI and was associated with early graft loss.

Outcomes in kidney transplant recipients treated with immediate-release tacrolimus capsules versus extended-release tacrolimus capsules: A cohort study.

Prior randomized trials and observational studies have generally reported similar outcomes in kidney transplant recipients (KTRs) treated with immediate-release tacrolimus (IR-TAC) versus extended-release tacrolimus (ER-TAC). However, many of these previous studies focused on patients with low immunological risks, had small sample sizes and brief follow-up periods, and excluded outcomes associated with graft loss, such as chronic rejection. To address these limitations, we conducted a cohort study of 848 KTRs at a single transplantation center who had generally high immunological risks and were treated with either IR-TAC capsules (589 patients, 65.9%) or ER-TAC capsules (289 patients, 34.1%). All patients received their designated maintenance immunosuppressive regimen for at least 3months post-transplantation. Afterwards, tacrolimus formulation was at the discretion of each patient's transplant nephrologist. For the two treatment groups, we compared the hazards of experiencing a composite outcome of acute or chronic antibody-mediated rejection (AMR), acute or chronic T-cell-mediated rejection, de novo DSA, and/or graft loss over a 3-year period starting at 3 months post-transplantation. In a multivariable Cox proportional hazards regression model, KTRs treated with IR-TAC capsules had an increased hazard of experiencing the composite outcome when compared to patients treated with ER-TAC capsules; however, this result was not significant (adj HR 1.24, 95% CI .92-1.68, p=.163). Similar results were obtained with inverse probability of treatment weighting (IPTW) using a propensity score (adj HR 1.25, 95% CI .93-1.68, p=.146). These findings suggest that when compared to IR-TAC capsules, ER-TAC capsules do not reduce the hazard of poor outcomes in KTRs with generally high immunological risks.

Perturbations of the T-cell immune repertoire in kidney transplant rejection.

In this cross-sectional and longitudinal analysis of mapping the T-cell repertoire in kidney transplant recipients, we have investigated and validated T-cell clonality, immune repertoire chronology at rejection, and contemporaneous allograft biopsy quantitative tissue injury, to better understand the pathobiology of acute T-cell fraction, T-cell repertoire and antibody-mediated kidney transplant rejection. To follow the dynamic evolution of T-cell repertoire changes before and after engraftment and during biopsy-confirmed acute rejection, we sequenced 323 peripheral blood samples from 200 unique kidney transplant recipients, with (n=100) and without (n=100) biopsy-confirmed acute rejection. We report that patients who develop acute allograft rejection, have lower (p=0.01) T-cell fraction even before transplantation, followed by its rise after transplantation and at the time of acute rejection accompanied by high TCR repertoire turnover (p=0.004). Acute rejection episodes occurring after the first 6 months post-transplantation, and those with a component of antibody-mediated rejection, had the highest turnover; p=0.0016) of their T-cell repertoire. In conclusion, we validated that detecting repertoire changes in kidney transplantation correlates with post-transplant rejection episodes suggesting that T-cell receptor sequencing may provide recipient pre-transplant and post-transplant predictors of rejection risk.

Acute antibody-mediated rejection of kidney allograft; mind the fibrin thrombi

Acute antibody-mediated rejection of kidney allograft; mind the fibrin thrombi

Circulating microRNAs in cellular and antibody-mediated heart transplant rejection.

Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.

S3324 An Unusual Case of Chronic Rejection Following Liver Transplant Due to Autoantibody Formation During Pregnancy

Introduction: We present a unique case of chronic rejection due to HLA-antibody formation during pregnancy. Case Description/Methods: A 51-year-old female with a history of autoimmune hepatitis received a live donor liver transplant (LDLT) with her husband as the donor in January 2008. HLA crossmatch testing was performed prior to transplant with a negative result. Patient was well overall for 8 years following liver transplant. Moderate elevation of liver enzymes during this period lead to liver biopsies consistent with autoimmune hepatitis but no evidence of acute rejection. Patient became pregnant 8 years after LDLT. She developed moderate-chronic elevation of liver enzymes during pregnancy with the most prominent peaks being 731 IU/L alkaline phosphatase (N: 40-140 IU/L), 200 IU/L aspartate aminotransferase (N: < 35 IU/L), and 160 IU/L alanine aminotransferase (N: < 52 IU/L). In December 2016, the patient had a liver biopsy displaying microvesicular steatosis, endotheliitis, and bile duct damage representative of acute cellular rejection. The patient was placed on quadruple immunosuppression therapy: everolimus, tacrolimus, prednisone, and mycophenolate mofetil. HLA antibody testing was performed at that time to check for donor specific antibodies (DSA). DSA was identified against HLA DQ6, suggesting sensitization to her husband’s HLA antigens that occurred during pregnancy/delivery. Despite extensive treatment, chronic rejection of the liver transplant prevailed with bile duct damage progressing to ductopenia. Additional treatments for her condition included intravenous immunoglobulin (IVIG) therapy every 28 days, with photopheresis and plasmapheresis to reduce leukocytes and immunoglobulins attacking the transplanted liver respectively. However, even with multi-modal therapy, the patient’s condition worsened indicated by a rising MELD (model of end-stage liver disease) score and bilirubin concentration to 8 mg/dL. Discussion: We present a unique case of acute (antibody-mediated) rejection progressing to chronic rejection in a LDLT patient following pregnancy due to sensitization to donor HLA DQ6. Consistent post-transplant HLA antibody testing should be a consideration for LDLT patients for early detection and treatment of DSA before memory B-cell production allows rejection to become chronic. Testing is especially important for monitoring female patients with LDLTs from spouse due to risk of blood exposure during pregnancy.