Startseite Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
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Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study

  • Necip Altundaş , Eda Balkan EMAIL logo , Murat Kizilkaya , Nurhak Aksungur , Salih Kara , Elif Demirci , Ercan Korkut , Gürkan Öztürk und Hakan Dursun
Veröffentlicht/Copyright: 22. März 2025
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Aus der Zeitschrift Open Life Sciences Band 20 Heft 1

Abstract

This study investigates the role of donor-specific antibodies (DSAs) in liver transplantation outcomes, focusing on their effects on liver damage. Ninety-four patients who underwent liver transplantation between 2019 and 2024 at Atatürk University were included. DSA testing was performed using the Luminex QIAGEN LifeCodes method. Patient demographic data, laboratory results, clinical conditions, and biopsy findings were analyzed. Disease-specific analyses were conducted for Wilson’s disease, autoimmune hepatitis, hepatocellular carcinoma (HCC), and hepatitis B virus (HBV). Due to the limited sample size, larger validation studies are needed, and the impact of the COVID-19 pandemic on the data collection process was considered. At the end of 1 year, persistent DSA had no significant effect on liver damage. However, early DSA positivity, particularly persistence and titration, requires further investigation. In Wilson’s disease, two DSA-positive patients (mean fluorescence intensity [MFI] 1,000–1,500) showed no damage. Among autoimmune hepatitis patients, 5 of 19 were DSA positive (MFI 1,700–5,600), with no detected damage. Four HCC patients were DSA positive (MFI 1,300–2,200). Among HBV patients, 12 of 31 were DSA positive, and 5 experienced liver damage. Tacrolimus levels in the third month were statistically associated with bilirubin levels. Prospective studies are needed to further clarify the clinical significance of DSA.

Keywords: liver transplant immunology; donor-specific antibodies; graft rejection mechanisns; chronic allograft dysfunction; molecular biomarkers in transplantation

1 Introduction

Liver transplantation has become the main treatment method for end-stage liver disease, with better outcomes being achieved in recent years. Therefore, improving the management of long-term complications, especially chronic antibody-mediated rejection (AMR), is the next challenge to overcome to maintain a good quality of life for liver transplant recipients [1].

The liver is recognized as an immune-privileged organ with anergy (lack of immune response) to many antigens and high immune tolerance. The incidence of AMR after liver transplantation is estimated to be about 1%, much lower than with heart (10–30%) and kidney (20–50%) transplantation [2,3]. Over the past decade, however, several research groups have noted that donor-specific antibodies (DSAs) are associated with chronic rejection. DSAs were reported to be linked to increased rates of liver fibrosis in liver transplant patients followed long term. This indicates the effect of AMR on liver allografts [4,5].

The contribution of anti-human leukocyte antigen (HLA) DSAs to organ rejection and allograft loss is now well documented in kidney, heart, lung, and liver transplants. The introduction of solid-phase analysis technology in the last decade revolutionized the detection and characterization of DSAs and made the method clinically feasible, leading to it becoming the standard of care in the pre- and post-transplant periods [6,7].

The Sensitization in Transplantation: Assessment of Risk (STAR) working group called for the clinical evaluation of alloimmune risks before and after transplantation in their 2017 report. Two types of alloimmune risks were identified in this report: alloimmune memory risk and de novo/naive response. The report also discussed how to use HLA typing and anti-HLA antibody tests to more precisely assess patient risk, provided recommendations for transplant programs, and outlined appropriate pre- and post-transplant clinical evaluation methods [8].

The 2019 STAR report examined the clinical applicability and limitations of existing tests for the assessment of alloimmune risk and emphasized the importance of tests evaluating anti-HLA antibody characteristics as a clinical diagnostic and research tool, the potential clinical value of tests measuring alloimmune T- and B-cell memory, and the development of HLA molecular mismatch scores as a prognosis tool. It also reported the clinical validity of DSA tests and stated that DSAs that form after transplantation are strongly associated with graft rejection. The group stated that these tests are widely used in pre- and post-transplantation risk assessment and are regarded as an important endpoint in next-generation clinical trials [9,10].

The earlier 2017 STAR report recommended that the evaluation of anti-HLA antibodies be performed using solid-phase assays and include all major HLA Class I and II loci (HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1/DQB1, -DPA1/DPB1) [11,12]. In addition, threshold values for anti-HLA antibody positivity were defined as the range of 1,000–1,500 mean fluorescence intensity (MFI) as universal cut-off values. Preformed DSA was defined as an antibody detected pre-transplant or between 2 weeks and 3 months post-transplant, while de novo DSA was defined as a new antibody that appears after 3 months post-transplant. Recent studies have investigated higher-resolution HLA genotyping to improve DSA risk assessment, evaluating whether DSAs occur pre- or post-transplant and the impact of the presence or loss of post-transplant DSA on graft damage and transplant outcomes. This more precise definition of DSA status is important in defining different forms of AMR and their onset time in liver transplant patients [13].

Although the presence of DSAs is generally less harmful in the context of liver transplantation than with other organ transplants such as kidney and heart, they may adversely affect liver graft function in certain circumstances. In particular, high levels of DSAs may increase the risk of post-transplant chronic graft dysfunction and fibrosis [14].

Therefore, DSA assessment in liver transplant recipients is particularly important for patients who have or are at risk of developing graft dysfunction. Although routine DSA screening is not a standard practice for all liver transplant patients, it is recommended for patients in whom graft health may be affected. This screening can be performed during protocol biopsies or based on specific clinical indicators such as changes in graft function [14].

The aim of this study was to comprehensively investigate the presence of DSAs and the potential effects of these antibodies on graft health in patients with various hepatic diseases undergoing liver transplantation. In particular, by investigating the effects of DSAs on complications such as deterioration in graft function, rejection, and fibrosis, we aimed to contribute to the development of strategies to optimize post-transplant patient management.

2 Materials and methods

2.1 Study population

This study was conducted collaboratively by the Atatürk University Departments of General Surgery (organ transplantation), Internal Medicine, Medical Biology, and Pathology at Atatürk University Yakutiye Hospital. The study included 94 patients diagnosed with primary hepatocellular carcinoma (HCC), alveolar viral hepatitis B (HBV), cryptogenic hepatitis, autoimmune hepatitis, or Wilson disease, as well as their respective liver donors. There were 48 males (54%) and 46 females (49%) in the patient group and 54 males (55%) and 40 females (45%) in the donor group. The mean age of the patients was 45.72 ± 16.99 years. The research protocol was explained to all participants and an informed consent form was signed before the study.

The patient group underwent a comprehensive battery of tests for the diagnosis of liver disease. These tests play a critical role in determining disease type, severity, and management strategies. First, blood tests were done to assess liver function, specifically examining liver damage by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzyme levels. Diseases of the bile ducts were assessed using alkaline phosphatase (ALP) and gamma-glutamyl transferase, and bilirubin metabolic capacity was assessed with jaundice with bilirubin tests. In addition, the ability of the liver to produce proteins and clotting factors was evaluated with albumin and prothrombin time tests. Hepatitis virus and autoantibody tests were conducted to evaluate for viral and autoimmune hepatitis. In terms of imaging methods, liver ultrasound was performed to evaluate liver size, anatomical deformities, and fluid accumulations. Detailed images of the liver were also obtained by computed tomography and magnetic resonance imaging to obtain information about tumors and other abnormalities. In addition, the stiffness of the liver was measured by elastography as part of the assessment for diseases such as fibrosis and cirrhosis. Disease type and severity were also confirmed by microscopic examination of percutaneous liver biopsy specimens. Imaging of the bile and pancreatic ducts was conducted with methods such as endoscopic retrograde cholangiopancreatography and endoscopic ultrasonography.

The study included 94 patients who underwent post-transplant DSA measurements. For patients who received transplants from deceased donors, the DSA molecular test was performed pre-transplantation, while those who received transplants from living donors underwent DSA testing only after transplantation. Patients who died after transplantation were not included in the study. In the post-transplant immunosuppression protocol, steroid therapy was tapered over the first 6 months, aiming for complete discontinuation within the first year after transplantation. In the long term, dual immunosuppressive therapy consisting of calcineurin inhibitor and mycophenolate mofetil was continued. Patients with rejection were treated with rituximab and steroid therapy. This treatment strategy aimed to effectively control the immune response of patients and minimize the risk of rejection.

Patients were followed up for an average of 5 years after liver transplantation, and their demographic, clinical, immunological, and histopathological data were obtained from medical records. In the first year after transplantation, retrospective and prospective evaluations were performed based on a protocol including immunosuppression therapy, de novo DSA screening, and allograft biopsies. However, variations in immunosuppression therapy and some missing data limit the evaluation of treatment adherence and immunosuppression.

During the study, a carefully planned method was implemented to minimize the effect of confounders. Participants were assigned or matched to groups based on factors such as disease type, age, sex, and other clinical characteristics. This approach aimed to reduce the impact of potential confounding variables. In addition, during data analysis, detailed statistical analyses were performed to accurately evaluate the effects of factors such as liver diseases and transplant history on the groups. The effects of these variables on the results were minimized by taking inequalities into consideration. These measures aimed to minimize the effects of confounders and increase the reliability of the study.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has been complied with all the relevant national regulations and institutional policies and in accordance with the tenets of the Helsinki Declaration and has been approved by the Ethics Committee of Atatürk University Faculty of Medicine (approval no: B.30.2.ATA.0.01.00/162; Erzurum, Türkiye).

2.2 Pathologic studies: post-transplant liver biopsy evaluation

The reports of post-transplant liver biopsies performed between 2019 and 2024 at the Department of Pathology of Atatürk University Faculty of Medicine were obtained from the archives for re-evaluation. Prepared archive slides consisted of hematoxylin and eosin (H&E)-stained slides, histochemical slides (Masson’s trichome, reticulin, rhodamine, Perls Prussian blue stains), and immunohistochemical slides (C4d, cytokeratin 7, CD68, CD4, CD8). On examination of the H&E slides, portal inflammation, the dominant inflammatory cell type, and lobular inflammation were evaluated and scored using the modified hepatic activity index (HAI) criteria. The H&E and immunohistochemical slides were evaluated together for central venulitis, portal venulitis, bile duct loss in the portal area, age-related findings in bile duct epithelium (epithelial cell hyperchromasia, nucleolus prominence, cellular disorganization) according to the Banff criteria. Additionally, c4D-stained slides were evaluated immunohistochemically for AMR according to the Banff criteria.

2.3 Molecular studies: donor-specific antibody (DSA) protocol

This study was designed to investigate the relationships between de novo DSA formation and the primary etiology of liver disease, demographic and laboratory results, the impact of de novo DSA on graft histology, the effect of immunosuppressive therapy on DSA development in the graft, and the number of biopsy-confirmed rejection events associated with de novo DSA.

Between 2019 and 2024, only DSA levels (expressed as MFI values) were used to evaluate immune responses. In this process, HLA antibodies with an MFI value >1,000 were considered positive. Serum samples were obtained within 1 year after transplantation and analyzed using Luminex-based systems according to the manufacturer’s instructions. For deceased donor transplants, the DSA test was performed before transplantation, and additional tests were conducted as clinically necessary.

De novo DSA development was defined as the detection of new antibodies with MFI >1,000 at 1 year post-transplantation. DSAs were evaluated separately for major histocompatibility complex (MHC) Classes I and II.

The Qiagen cell isolation and DSA protocol used in this study was meticulously designed to ensure high accuracy and reliability in laboratory analyses. The protocol begins with the collection of blood samples into anticoagulant tubes, followed by centrifugation to separate plasma and cellular fractions. During this step, white blood cells are enriched and purified by removing plasma. The isolated cells are then cultured in the appropriate nutrient medium or cryogenically stored.

Serum or plasma samples prepared for DSA analysis are processed in the Qiagen Fluorescent Labeled Antibody Identification system to detect anti-HLA antibodies. This system is used to determine the presence and concentration of antibodies, with DSAs detected by measuring the MFI values. Throughout the analysis, the accuracy of the results is ensured through the use of standard controls and calibrations. The data obtained are evaluated according to clinical and laboratory standards, and the results are presented as clinical reports and research findings.

In this study, IgG-type antibodies were used for DSA measurements. These tests do not target specific antigens but instead detect antibodies against HLA Class I and Class II antigens. In the Luminex-based system analysis, Class I and Class II antibodies were evaluated separately, and the positivity for both classes was determined by MFI values. The Luminex Single Antigen panel was not used; instead, general antibody levels for Class I and Class II were measured.

DSA tests were performed on the Luminex device using the IMMUCOR DSA kit from Qiagen. The test was conducted in accordance with the protocol provided by the kit, with Class I and Class II antigens being evaluated in a general manner. The tests were analyzed under two main categories without examining each locus individually.

This protocol provides critical information for immunological and transplantation studies by ensuring high sensitivity and reliability in DSA detection and cell isolation. DSA measurements were conducted using IMMUCOR/LIFECODES brand systems (lot number 3014433), which are manufactured in the United States and were used according to the manufacturer’s instructions.

2.4 Statistical analysis

The data were analyzed with IBM SPSS Statistics version 23. The normality of data distributions was examined with the Shapiro–Wilk test. Connections between categorical variables were examined with the Fisher–Freeman–Halton test. One-way analysis of variance (ANOVA) was used to compare normally distributed data between three or more groups. The Kruskal–Wallis test was used to compare non-normally distributed data between three or more groups, followed by the Dunn test for multiple comparisons. Associations between independent risk factors and rejection were examined by binary logistic regression analysis. Results were presented as mean ± standard deviation or median and range for quantitative data and as frequency and percentage for categorical data. p < 0.05 was accepted as the level of statistical significance.

3 Results

A total of 94 patients who underwent their first liver transplantation at Erzurum Atatürk University Organ Transplantation Center between 2019 and 2024 were followed up with de novo DSA screening and allograft biopsy in the first year after transplantation. The patients were categorized according to diagnosis, and data regarding demographic characteristics, de novo DSA prevalence, risk factors, and allograft histology were presented for each diagnostic group. Demographic data and laboratory results were meticulously collected and information about the patients’ immunosuppressive drug therapy was recorded in detail. However, there were still some missing biopsy data and drug levels. As these missing data may pose a limitation when evaluating the efficacy of immunosuppressive therapies and biopsy results, the findings of this study should be interpreted with caution.

3.1 Demographic and transplant characteristics

Between 2019 and 2024, a total of 94 patients in our institution underwent their first liver transplantation from a living or deceased donor. The basic characteristics of the liver transplant recipients are detailed in Table 1. The study included patients diagnosed with primary HCC, alveolar disease, HBV, cryptogenic hepatitis, autoimmune hepatitis, or Wilson disease, as well as their respective liver donors. There were 48 males (54%) and 46 females (49%) in the patient group and 54 males (55%) and 40 females (45%) in the donor group. The mean age of the patients was 45.72 ± 16.99 years.

Table 1

Comparison of demographic and clinical data by diagnosis

Alveolar echinococcosis HBV HCC Cryptogenic hepatitis Autoimmune hepatitis Wilson disease Total Test statistic p
Age (years) 42.54 ± 16.38 51.25 ± 15.84 46.55 ± 12.11 44.57 ± 14.24 43.05 ± 19.08 30.2 ± 26.01 45.72 ± 16.99 1.788 0.124a
Transplant duration (years) 5 (1–10) 6 (0–12) 5 (1–11) 4.5 (1–10) 5 (0–12) 5 (5–10) 5 (0–12) 2.687 0.748b
Sex, n (%)
 Male 8 (61.5) 14 (43.8) 6 (54.6) 8 (57.1) 10 (52.6) 2 (40) 48 (51.1) 1.914 0.894c
 Female 5 (38.5) 18 (56.3) 5 (45.5) 6 (42.9) 9 (47.4) 3 (60) 46 (48.9)
ALP (U/L) 118.9 (73–290) 132 (49.1–391.2) 161.73 (36–290) 88.95 (37.4–342.6) 112.7 (27–196.6) 191.5 (71–303.8) 118.9 (27–391.2) 3.612 0.607b
AST (U/L) 22.8 (8.4–39.5) 22.4 (12.8–2,550.1) 30.5 (8.4–39.4) 23.6 (14.6–1,776.2) 23.5 (11.9–2,550.1) 20.9 (15.9–59.8) 22.8 (8.4–2,550.1) 3.385 0.641b
ALT (U/L) 21.6 (7–135.7) 25.9 (8.5–2,734.7) 28 (8–58) 24.2 (12.5–692.1) 29.7 (9.9–1,004.7) 20 (11.6–82) 25.9 (7–2,734.7) 5.333 0.377b
Total bilirubin (mg/dL) 0.95 (0.41–2.75) 0.91 (0.29–14.51) 0.82 (0.34–2.65) 0.84 (0.43–2.59) 0.84 (0.54–14.51) 0.71 (0.42–1.19) 0.84 (0.29–14.51) 2.351 0.799b
Direct bilirubin (mg/dL) 0.23 (0.11–1.24) 0.22 (0.06–9.22) 0.22 (0.07–1.29) 0.2 (0.1–0.88) 0.19 (0.1–9.22) 0.14 (0.11–0.29) 0.21 (0.06–9.22) 4.366 0.498b

Values are represented as n (%), mean ± standard deviation, and median (range).

aOne-way ANOVA.

bKruskal–Wallis H test.

cFisher–Freeman–Halton test.

Abbreviations: HBV: viral hepatitis B, HCC: hepatocellular carcinoma, ALP: alkaline phosphatase, AST: aspartate transaminase, ALT: alanine transaminase.

There was no statistically significant difference in mean age according to diagnosis (p = 0.124). The mean age was 42.54 years in the alveolar disease group, 51.25 years in the HBV group, 46.55 years in the HCC group, 44.57 years in the cryptogenic hepatitis group, 43.05 years in the autoimmune hepatitis group, and 30.2 years in the Wilson disease group. There was no statistically significant difference in median transplant time according to diagnosis (p = 0.748). The median time was 4.5 years among patients with cryptogenic hepatitis; 5 years for patients with alveolar disease, HCC, autoimmune hepatitis, and Wilson disease; and 6 years in patients with HBV.

There was no statistically significant difference between the diagnostic groups in terms of median ALP value (p = 0.607). The median ALP level was 118.9 in the alveolar disease group, 132 in the HBV group, 161.73 in the HCC group, 88.95 in the cryptogenic hepatitis group, 112.7 in the autoimmune hepatitis group, and 191.5 in the Wilson disease group. There were also no statistically significant differences in median AST or ALT values according to diagnosis (p = 0.641 and p = 0.377, respectively). The median AST and ALT levels were 22.8 and 21.6 among patients with alveolar disease, 22.4 and 25.9 among those with HBV, 30.5 and 28 among those with HCC, 23.6 and 24.2 for cryptogenic hepatitis, 23.5 and 29.7 for autoimmune hepatitis, and 20.9 and 20 among patients with Wilson disease, respectively. Similarly, median total bilirubin and direct bilirubin levels showed no significant difference among the diagnostic groups (p = 0.799 and p = 0.498, respectively). The median total and direct bilirubin values were 0.95 and 0.23 in the alveolar disease group, 0.91 and 0.22 in the HBV group, 0.82 and 0.22 in the HCC group, 0.84 and 0.20 in the cryptogenic hepatitis group, 0.84 and 0.19 in the autoimmune hepatitis group, and 0.71 and 0.14 in the Wilson disease group. There was no statistically significant relationship between sex and diagnosis (p = 0.894) (Table 1).

3.1.1 De novo DSA Class I and Class II classifications and MFI values of liver transplant patients according to diagnosis

The distribution of de novo DSA positivity and MFI values by diagnostic group are presented in Table 2. There were no statistically significant differences between the diagnostic groups in the distribution of Class I (p = 0.972), Class II (p = 0.901), or Class I and Class II (p = 0.934) de novo DSA positivity.

Table 2

Comparison of Class I and II DSAs and MFI values according to diagnosis

Parameter Alveolar echinococcosis HBV HCC Cryptogenic hepatitis Autoimmune hepatitis Wilson disease Total Test statistic p
Class I
 Negative 11 (84.6) 25 (78.1) 10 (90.9) 11 (78.6) 16 (84.2) 4 (80) 77 (81.9) 1.329 0.972a
 Positive 2 (15.4) 7 (21.9) 1 (9.1) 3 (21.4) 3 (15.8) 1 (20) 17 (18.1)
Class II
 Negative 9 (69.2) 21 (65.6) 7 (63.6) 9 (64.3) 15 (79) 3 (60) 64 (68.1) 1.807 0.901a
 Positive 4 (30.8) 11 (34.4) 4 (36.4) 5 (35.7) 4 (21.1) 2 (40) 30 (31.9)
Classes I and II
 Negative 9 (69.2) 20 (62.5) 7 (63.6) 8 (57.1) 14 (73.7) 3 (60) 61 (64.9) 1.509 0.934a
 Positive 4 (30.8) 12 (37.5) 4 (36.4) 6 (42.9) 5 (26.3) 2 (40) 33 (35.1)
Class I MFI 364 (62–1,559) 574 (24–4,383) 443 (134–2,160) 385 (39–4,431) 500 (133–4,498) 457 (287–1,552) 456 (24–4,498) 1.813 0.874b
Class II MFI 559 (65–2,913) 652 (60–7,310) 648 (213–1,876) 666.5 (59–5,477) 530 (123–5,514) 564 (479–1,452) 589 (59–7,310) 1.486 0.915b

Values are represented as n (%), mean ± standard deviation, and median (range).

aFisher–Freeman–Halton test.

bKruskal–Wallis H test.

The median MFI values for Class I DSAs did not differ by diagnosis (p = 0.874). The median values were 364 for alveolar disease, 574 for HBV, 443 for HCC, 385 for cryptogenic hepatitis, 500 for autoimmune hepatitis, and 457 for Wilson disease. Similarly, there was no statistically significant difference in median MFI values of Class II DSAs according to diagnosis (p = 0.915). The median values were 559 for alveolar disease, 652 for HBV, 648 for HCC, 666.5 for cryptogenic hepatitis, 530 for autoimmune hepatitis, and 564 for Wilson disease (Table 2).

3.1.2 Pathological biopsy findings in liver transplant patients according to diagnosis

Rejection status and other biopsy findings are compared between the diagnostic groups in Table 3. Overall, 73.4% of the patients had rejection and 26.6% did not. Differences in the frequency of rejection were observed between the groups, but the difference did not reach statistical significance (p = 0.069).

Table 3

Comparison of rejection and liver biopsy results according to diagnosis

Parameter Alveolar echinococcosis HBV HCC Cryptogenic hepatitis Autoimmune hepatitis Wilson disease Total Test statistic p
Rejection status
 No 11 (84.6) 24 (75) 10 (90.9) 6 (42.9) 13 (68.4) 5 (100) 69 (73.4) 9.756 0.069a
 Yes 2 (15.4) 8 (25) 1 (9.1) 8 (57.1) 6 (31.6) 0 (0) 25 (26.6)
Portal inflammation severity
 1 1 (20) 3 (37.5) 0 (0) 1 (16.7) 1 (25) — 6 (24) 10.380 0.639a
 2 1 (20) 2 (25) 2 (100) 3 (50) 2 (50) — 10 (40)
 3 3 (60) 1 (12.5) 0 (0) 2 (33.3) 0 (0) — 6 (24)
 4 0 (0) 2 (25) 0 (0) 0 (0) 1 (25) — 3 (12)
Lobular inflammation
 K1 1 (20) 1 (16.7) 1 (50) 1 (20) 1 (50) — 5 (25) 7.183 0.556a
 K2 3 (60) 1 (16.7) 1 (50) 1 (20) 1 (50) — 7 (35)
 K3 1 (20) 4 (66.7) 0 (0) 3 (60) 0 (0) — 8 (40)
Fibrosis
 2 3 (75) 1 (16.7) 0 (0) 1 (20) 1 (50) — 6 (31.6) 13.207 0.189a
 3 1 (25) 1 (16.7) 2 (100) 3 (60) 0 (0) — 7 (36.8)
 4 0 (0) 1 (16.7) 0 (0) 1 (20) 1 (50) — 3 (15.8)
 5 0 (0) 3 (50) 0 (0) 0 (0) 0 (0) — 3 (15.8)
Ductulitis
 No 13 (100) 32 (100) 11 (100) 9 (64.3) 16 (84.2) 5 (100) 86 (91.5) 14.411 0.001a
 Yes 0 (0) 0 (0) 0 (0) 5 (35.7) 3 (15.8) 0 (0) 8 (8.5)
Central venulitis
 No 13 (100) 32 (100) 11 (100) 11 (78.6) 17 (89.5) 5 (100) 89 (94.7) 8.239 0.041a
 Yes 0 (0) 0 (0) 0 (0) 3 (21.4) 2 (10.5) 0 (0) 5 (5.3)
Portal venulitis
 No 13 (100) 32 (100) 11 (100) 10 (71.4) 16 (84.2) 5 (100) 87 (92.6) 11.635 0.009a
 Yes 0 (0) 0 (0) 0 (0) 4 (28.6) 3 (15.8) 0 (0) 7 (7.4)
Bile duct loss
 No 13 (100) 32 (100) 11 (100) 11 (78.6) 19 (100) 5 (100) 91 (96.8) 8.936 0.015a
 Yes 0 (0) 0 (0) 0 (0) 3 (21.4) 0 (0) 0 (0) 3 (3.2)
Hyperchromatosis
 No 13 (100) 30 (93.8) 10 (90.9) 9 (64.3) 17 (89.5) 5 (100) 84 (89.4) 8.468 0.068a
 Yes 0 (0) 2 (6.3) 1 (9.1) 5 (35.7) 2 (10.5) 0 (0) 10 (10.6)
Nucleolus
 No 13 (100) 30 (93.8) 10 (90.9) 9 (64.3) 17 (89.5) 5 (100) 84 (89.4) 8.468 0.068a
 Yes 0 (0) 2 (6.3) 1 (9.1) 5 (35.7) 2 (10.5) 0 (0) 10 (10.6)
Cellular disorganization
 No 13 (100) 30 (93.8) 10 (90.9) 9 (64.3) 17 (89.5) 5 (100) 84 (89.4) 8.468 0.068a
 Yes 0 (0) 2 (6.3) 1 (9.1) 5 (35.7) 2 (10.5) 0 (0) 10 (10.6)
C4d
 C4d negative 0 (0) — 1 (100) 4 (100) 2 (100) — 7 (87.5) — —
 C4d positive 1 (100) — 0 (0) 0 (0) 0 (0) — 1 (12.5)
Pathological diagnosis
 Acute rejection 1 (100) 0 (0) 0 (0) 0 (0) 0 (0) — 1 (6.3) 18.896 0.491a
 Acute cellular rejection 0 (0) 0 (0) 0 (0) 1 (14.3) 1 (20) — 2 (12.5)
 Early chronic T-cell-mediated rejection 0 (0) 1 (50) 1 (100) 5 (71.4) 3 (60) — 10 (62.5)
 Steatohepatitis 0 (0) 1 (50) 0 (0) 0 (0) 1 (20) — 2 (12.5)

Values are represented as n (%).

aFisher–Freeman–Halton test.

The severity of portal inflammation was rated in four categories. The distribution of patients according to this severity rating (from 1 to 4) was 24, 40, 24, and 12%, respectively. There was no significant difference in portal inflammation severity (p = 0.639). Lobular inflammation was rated in three categories, K1, K2, and K3. The distribution of patients in these categories was 25, 35, and 40%, respectively. Lobular inflammation did not differ significantly between the groups (p = 0.556). The severity of fibrosis was graded as 2, 3, 4, and 5. According to the severity rating, the distribution of fibrosis was 31.6, 36.8, 15.8, and 15.8%, respectively. Fibrosis severity did not differ significantly (p = 0.189) (Table 3).

3.1.3 Immunosuppressant drug serum levels of recipients after liver transplantation

Immunosuppressant drug levels did not differ statistically overall or according to diagnosis (Table 4).

Table 4

Immunosuppressant drug levels at 1, 3, and 6 months post-transplant

Drug Alveolar echinococcosis HBV HCC Cryptogenic hepatitis Autoimmune hepatitis Wilson disease Total Test statistic p
1-month TAC (UL) 6.37 (3.6–15) 8.37 (3.6–13.2) 7.11 (6.24–19.1) 8.8 (4.5–14.1) 7.19 (2.6–10.76) 7.8 (5.5–13.23) 7.38 (2.6–19.1) 8.145 0.148a
3-month TAC (UL) 8.1 (5.83–15.52) 9.15 (5.5–14.8) 8.3 (6.07–12.4) 9.69 (4.65–12.18) 9.2 (1.78–12.67) 8.1 (4.9–9.8) 8.87 (1.78–15.52) 3.324 0.650a
6-month TAC (UL) 8.6 ± 2.39 8.69 ± 2.1 8.75 ± 2.24 9.28 ± 1.59 8.54 ± 2.27 7.02 ± 1.76 8.65 ± 2.11 0.857 0.514b
Basiliximab (µg/L) 0.30–9.27 0.24–7.40 0.92–6.48 0.23–4.68 0.30–9.20 0.65–8.87 0.21–7.44 0.38–8.00 0.436b

Values are represented as mean ± standard deviation and median (range).

aKruskal–Wallis H test.

bOne-way ANOVA.

Abbreviations: HBV: viral hepatitis B, HCC: hepatocellular carcinoma, TAC: tacrolimus.

There was no statistically significant difference in median tacrolimus levels among the diagnostic groups at post-transplant 1 month (p = 0.148). The median tacrolimus values at 1 month were 6.37 ng/mL in the alveolar disease group, 8.37 in the HBV group, 7.11 in the HCC group, 8.8 in the cryptogenic hepatitis group, 7.19 in the autoimmune hepatitis group, and 7.8 in the Wilson disease group. Similarly, these values did not differ at post-transplant 3 or 6 months (p = 0.650 and 0.514, respectively). At 3 and 6 months, the median tacrolimus values were 8.1 and 8.6 in the alveolar disease group, 9.15 and 8.69 in the HBV group, 8.3 and 8.75 in the HCC group, 9.69 and 9.28 in the cryptogenic hepatitis group, 9.2 and 8.54 in the autoimmune hepatitis group, and 8.1 and 7.02 in the Wilson disease group, respectively. There was also no statistically significant difference in basiliximab levels according to diagnosis (p = 0.436) (Table 4).

3.1.4 Demographic, laboratory, and immunosuppressant drug data according to the presence of post-transplant de novo DSAs

There was a statistically significant difference in direct bilirubin levels according to DSA class (p = 0.008). The median direct bilirubin levels were 0.88 in patients positive for Class I only, 0.27 in those who were positive for Class II only, and 0.19 in those positive for both Classes I and II. Significant differences were also observed in median MFI values when categorized according to DSA class. The median Class I MFI value showed no significant difference between patients positive for only Class I and those positive for both Classes I and II but was significantly lower in patients positive for Class II only (p < 0.001). Similarly, the median Class II MFI value did not differ significantly between patients positive for only Class II and those positive for both Classes I and II but was significantly lower among patients positive for Class I only (p = 0.016). No significant difference in the other demographic and clinical variables was observed according to DSA class (p > 0.05) (Table 5) (Figures 1–3).

Table 5

Comparison of quantitative data according to the presence of donor-specific antibodies against HLA Classes I and II

Class I only Class II only Classes I and II Test statistic p
Age (years) 53 (38–62) 45.5 (7–76) 57.5 (13–67) 2.001 0.368a
Transplant duration (years) 4 ± 6.08 5.88 ± 3.61 5.36 ± 2.87 0.369 0.694b
ALP 327.4 (84.3–342.6) 136 (36–196) 136.05 (27–391.2) 2.955 0.228a
AST (UL) 21.4 (20.2–1776.2) 19.3 (8.4–42) 24.15 (11.9–71) 2.900 0.235a
ALT (UL) 41 (11.6–692.1) 13.3 (8–83) 33.7 (9.9–168) 2.115 0.347a
Total bilirubin (mg/dL) 4.72 ± 4.48 1.32 ± 0.76 0.82 ± 0.3 3.390 0.121b
Direct bilirubin (mg/dL) 0.88 (0.57–5.54) a 0.27 (0.1–1.29)a.b 0.19 (0.1–0.56)b 9.572 0.008a
Class I MFI 2,234 (2,072–4,431)a 599 (134–976)b 1,989 (1,024–4,498)a 23.559 <0.001a
Class II MFI 276 (249–365)a 2,145 (1,153–5,477)b 2,044.5 (1,100–7,310)b 8.218 0.016a
1-Month TAC (U/L) 7.71 ± 0.65 8.26 ± 2.42 8.85 ± 3.17 0.306 0.739b
3-Month TAC (U/L) 9.76 ± 1.2 8.65 ± 2.68 9.39 ± 2.7 0.420 0.661b
6-Month TAC (U/L) 9.29 ± 0.85 8.01 ± 1.99 8.94 ± 1.95 1.148 0.331b

No difference between groups with the same letter. Values are represented as mean ± standard deviation and median (range).

aKruskal–Wallis H test.

bOne-way ANOVA.

Abbreviations: ALP: alkaline phosphatase, AST: aspartate transaminase, ALT: alanine transaminase, MFI: mean fluorescence intensity, TAC: tacrolimus.

Figure 1 Direct bilirubin levels in patients positive for DSAs against Class I and/or Class II HLA.
Figure 1

Direct bilirubin levels in patients positive for DSAs against Class I and/or Class II HLA.

Figure 2 Class I MFI values in patients positive for DSAs against Class I and/or Class II HLA.
Figure 2

Class I MFI values in patients positive for DSAs against Class I and/or Class II HLA.

Figure 3 Class II MFI values in patients positive for DSAs against Class I and/or Class II HLA.
Figure 3

Class II MFI values in patients positive for DSAs against Class I and/or Class II HLA.

3.1.5 Demographic and pathological findings according to the presence of post-transplant de novo DSAs

DSA class showed no significant relationship with categorical variables such as sex, donor type, rejection, and biopsy findings (p > 0.05) (Table 6).

Table 6

Comparison of characteristics according to the presence of donor-specific antibodies against HLA Classes I and II

Parameter Class I only Class II only Classes I and II Test statistic p
Donor
 Living 2 (66.7) 15 (93.8) 12 (85.7) 2.264 0.273a
 Deceased 1 (33.3) 1 (6.3) 2 (14.3)
Sex
 Male 1 (33.3) 10 (62.5) 6 (42.9) 1.652 0.515a
 Female 2 (66.7) 6 (37.5) 8 (57.1)
Rejection status
 No 2 (66.7) 12 (75) 9 (64.3) 0.693 0.862a
 Yes 1 (33.3) 4 (25) 5 (35.7)
Portal inflammation severity
 1 1 (100) 2 (40) 1 (20) 4.677 1.000a
 2 0 (0) 2 (40) 2 (40)
 3 0 (0) 0 (0) 1 (20)
 4 0 (0) 1 (20) 1 (20)
Lobular inflammation
 K1 1 (33.3) 0 (0) 1.956 0.648a
 K2 1 (33.3) 1 (25)
 K3 1 (33.3) 3 (75)
Fibrosis
 2 0 (0) 1 (33.3) 3 (60) 6.137 0.644a
 3 0 (0) 1 (33.3) 0 (0)
 4 0 (0) 0 (0) 1 (20)
 5 1 (100) 1 (33.3) 1 (20)
Ductulitis
 No 3 (100) 16 (100) 13 (92.9) — —
 Yes 0 (0) 0 (0) 1 (7.1)
Venulitis of central vein
 No 3 (100) 16 (100) 14 (100) — —
Venulitis of portal vein
 No 3 (100) 16 (100) 13 (92.9) — —
 Yes 0 (0) 0 (0) 1 (7.1)
Bile duct loss
 No 3 (100) 16 (100) 13 (92.9) — —
 Yes 0 (0) 0 (0) 1 (7.1)
Hyperchromatosis
 No 2 (66.7) 14 (87.5) 12 (85.7) 1.374 0.604a
 Yes 1 (33.3) 2 (12.5) 2 (14.3)
Nucleolus
 No 2 (66.7) 14 (87.5) 12 (85.7) 1.374 0.604a
 Yes 1 (33.3) 2 (12.5) 2 (14.3)
Cell disorganization
 No 2 (66.7) 14 (87.5) 12 (85.7) 1.374 0.604a
 Yes 1 (33.3) 2 (12.5) 2 (14.3)
Pathological diagnosis
 Steatohepatitis 0 (0) 0 (0) 1 (33.3)

Values are represented as n (%).

aFisher–Freeman–Halton test.

The association between independent risk factors and rejection was examined by binary logistic regression analysis using univariate and multivariate binary logistic regression models. Tacrolimus values at post-transplant 3 months were found to be significantly associated with rejection in the univariate and multivariate models (p = 0.010 and p = 0.030, respectively). With each unit increase in tacrolimus at 3 months, the odds of rejection were 1.353 times higher according to the univariate model and 1.337 times higher according to the multivariate model. Other variables showed no statistically significant association with rejection (p > 0.05) (Table 7).

Table 7

Binary logistic regression analysis of the association between independent risk factors and rejection

Rejection Univariate Multivariate
Negative Positive OR (95% CI) p OR (95% CI) p
Transplant type
 Living donor 63 (75) 21 (25) Reference
 Deceased donor 6 (60) 4 (40) 2 (0.514–7.778) 0.317 1.957 (0.334–11.481) 0.457
Diagnosis
 Alveolar echinococcosis 11 (84.6) 2 (15.4) — — — —
 Viral hepatitis B 24 (75) 8 (25) — — — —
 Hepatocellular carcinoma 10 (90.9) 1 (9.1) — — — —
 Cryptogenic hepatitis 6 (42.9) 8 (57.1) — — — —
 Autoimmune hepatitis 13 (68.4) 6 (31.6) — — — —
 Wilson disease 5 (100) 0 (0) — — — —
Class I — — — —
 Class I negative 58 (75.3) 19 (24.7) Reference
 Class I positive 11 (64.7) 6 (35.3) 1.665 (0.542–5.111) 0.373 0.594 (0.028–12.408) 0.737
 Class II
 Class II negative 48 (75) 16 (25) Reference
 Class II positive 21 (70) 9 (30) 1.286 (0.49–3.372) 0.609 1.144 (0.151–8.671) 0.896
Sex
 Male 34 (70.8) 14 (29.2) Reference
 Female 35 (76.1) 11 (23.9) 0.763 (0.304–1.915) 0.565 0.849 (0.26–2.771) 0.787
 Age 45.54 ± 18.11 46.24 ± 13.75 1.002 (0.976–1.03) 0.858 0.998 (0.963–1.035) 0.927
 ALP (U/L) 135.5 ± 76.59 158.05 ± 84.96 1.003 (0.998–1.009) 0.231 1 (0.992–1.008) 0.994
 AST (U/L) 90.8 ± 348.09 238.85 ± 712.02 1.001 (1–1.001) 0.210 0.997 (0.988–1.005) 0.447
 ALT (U/L) 84.21 ± 334.95 120.36 ± 274.55 1 (0.999–1.002) 0.639 1 (0.993–1.007) 0.994
 Total bilirubin (mg/dL) 1.06 ± 0.88 2.49 ± 4.15 1.304 (0.998–1.704) 0.052 0.589 (0.093–3.711) 0.573
 Direct bilirubin (mg/dL) 0.34 ± 0.53 1.29 ± 2.68 1.566 (0.985–2.489) 0.058 9.482 (0.408–220.581) 0.161
 Class I MFI 725.01 ± 916.05 1070.54 ± 1208.97 1 (1–1.001) 0.158 1.001 (0.999–1.002) 0.329
 Class II MFI 1094.68 ± 1404.4 1157.04 ± 1235.28 1 (1–1) 0.845 1 (0.999–1.001) 0.526
 1-Month TAC (ng/mL) 7.8 ± 3.02 8.89 ± 2.2 1.139 (0.971–1.335) 0.110 1.1 (0.907–1.333) 0.333
 3-Month TAC (ng/mL) 8.68 ± 2.1 10.09 ± 2.37 1.353 (1.075–1.702) 0.010 1.337 (1.029–1.737) 0.030
 6-Month TAC (ng/mL) 8.46 ± 2.18 9.2 ± 1.82 1.187 (0.948–1.485) 0.135 1.121 (0.818–1.536) 0.477

Abbreviations: OR: odds ratio, CI: confidence interval, ALP: alkaline phosphatase, AST: aspartate transaminase, ALT: alanine transaminase, MFI: mean fluorescence intensity, TAC: tacrolimus.

4 Discussion

Our knowledge of DSAs in liver transplant recipients has evolved significantly over the past decade, and DSAs are no longer considered clinically insignificant to liver transplant outcomes.

4.1 Literature

In a 2012 study investigating the prevalence, development, and effects of anti-HLA DSAs in liver transplant patients, Taner et al. examined the frequency of DSAs at 1 year post-transplant and how these antibodies changed over time. They observed that DSAs were rare in the patient population and disappeared in most patients over time, noting that the presence of DSAs did not have a significant negative effect on transplant outcomes [15].

Vandevoorde et al. investigated the prevalence of DSAs after adult liver transplantation, the risk factors for their development, and the effects of these antibodies on transplantation outcomes. They determined that the presence of DSA can potentially lead to complications and unfavorable outcomes after liver transplantation but noted that these negative effects can vary from patient to patient [16].

In a 2013 study, O’Leary et al. reported that preformed Class II DSAs significantly increased the risk of rejection in the early post-transplant period [17]. Another 2013 study by Kaneku et al. revealed that de novo anti-HLA DSAs significantly reduced both patient and graft survival [18].

Del Bello et al. investigated how newly developed anti-HLA DSAs cause rejection reactions in liver transplant patients. Their findings indicated that the presence of de novo antibodies may trigger post-transplant rejection events, which can impact patients’ clinical course. The authors stated that de novo DSA monitoring is critical to increase post-transplant success [19].

In an earlier 2014 study, Del Bello et al. investigated the prevalence and incidence of DSA antibodies in post-liver transplant care patients and the risk factors associated with DSA. They found that DSAs are common and identified certain risk factors associated with antibody development [20].

Another study by O’Leary et al. examined the effects of post-transplant DSAs on the progression of liver fibrosis in liver transplant patients infected with the hepatitis C virus. They reported that DSAs can accelerate the development of fibrosis after liver transplantation and this may have negative effects on patients’ long-term health outcomes. The authors emphasized that anti-HLA antibodies are critically important, especially in transplant patients with hepatitis C infection [21].

A 2016 study by Ducreux et al. investigated the methods used to monitor the effectiveness of the treatment of humoral rejection after liver transplantation. The efficacy of Luminex single antigen tests and complement binding properties in this monitoring process was evaluated. The authors stated that Luminex tests may be useful, but the effectiveness of these tests should be confirmed by more clinical studies [22].

In another study examining DSA presence, risk factors, and long-term effects, preformed DSA was detected in 8 patients (24.2%) but titers of these antibodies were negative after 5 years and no adverse events occurred. Eight (33.3%) of the other 24 patients developed de novo DSA, but only 2 patients remained Class II DSA-positive with high MFI at 5 years. There was no significant relationship between DSA development and the risk of rejection, graft loss, or mortality [23].

In a study by Liu et al. examining the role of DSAs in graft survival after pediatric liver transplantation, DSA positivity was detected in 10 (20.8%) of 48 patients and AMR was observed in 4 patients. The authors concluded that DSA positivity was an independent risk factor for liver failure and long-term mortality [24].

Kovandova et al. revealed in their study that de novo HLA Class II antibodies were associated with chronic AMR but not acute AMR after liver transplantation [25].

A retrospective study evaluating the frequency, developmental risk factors, and effects of anti-HLA DSAs in adults after first liver transplantation between 2000 and 2010 showed that the presence of DSAs did not significantly impact patient or graft survival. DSAs were detected in a minority of adult liver transplant patients and were reported to generally have a limited impact on graft and patient outcomes [16].

A systematic review and meta-analysis by Beyzaei et al. examined the effects of de novo DSA on acute and chronic rejection rates and long-term graft survival. The results indicated that de novo DSA may increase the risk of graft rejection and loss [26].

The study by Beyzaei et al. focused on the effect of de novo DSAs on long-term liver transplant outcomes. Although it provided specific findings on the effects of de novo DSAs on clinical outcomes, data regarding MFI values were not included in the study.

In a 2019 study by Jucaud et al., de novo DSA development was detected in 69 liver transplant patients. Only adult and pediatric patients receiving calcineurin inhibitor monotherapy were included in the study. MFI values were considered positive above 1,000, but specific findings and details were not reported [27].

In their 2022 study, Pinon et al. found a high rate of de novo DSA positivity in pediatric liver transplant patients. The study revealed that de novo DSAs were common in these patients, potentially affecting long-term transplant outcomes. However, the study did not specifically include detailed reports on the clinical effects of de novo DSAs [28].

There is no widely accepted significant MFI threshold value associated with high risk for patients undergoing liver transplantation [27,29]. However, in small-scale studies using lower MFI threshold values, there was generally no association with clinically significant adverse events. Clinical scoring systems based on DSA and MFI have been suggested to improve the prediction of long-term liver allograft survival in patients with chronic AMR lesions. Additional molecular antibody and complement binding assays may aid in predicting liver allograft fibrosis and the risk of acute and chronic rejection. However, there are limited studies evaluating these tests in the context of liver allograft loss [20,30,31].

In most studies, regardless of being preformed or de novo, DSA positivity was associated with more allograft inflammation and fibrosis, but studies in which preformed DSAs became negative after transplantation did not confirm these relationships. HLA epitope mismatch scores may help identify liver patients at higher risk of developing de novo DSA, but the results are preliminary. As with other organ transplants, nonadherence to drug therapy and inadequate immunosuppression can significantly impact DSA incidence and risk.

It is also worth noting that bilirubin levels are an important marker in DSA-positive patients. DSA positivity should be evaluated as a clinically relevant biomarker and clinicians should be aware that elevated bilirubin levels can lead to liver damage and seriously threaten graft survival in DSA-positive transplant patients. Therefore, regular pathological examinations and periodic DSA tests during the follow-up of these patients may be critical in maintaining graft survival.

Furthermore, DSA positivity was observed to have no direct effect on immunosuppression therapy. The current literature suggests that higher MFI values (>1,000) are associated with adverse histological changes in the liver allograft. This fact may improve long-term survival prediction with clinical scoring systems.

In the present study, a statistically significant relationship between DSA positivity and risk of rejection or liver damage was not observed. This finding shows that DSA positivity is not directly associated with the expected negative outcomes in this patient group. However, there are reports in the literature suggesting that DSA should be considered as a potential biomarker in clinical management, so clinicians should keep in mind that this result may differ in specific patient subgroups.

5 Conclusion

This study evaluated the effects of DSA positivity on the graft in liver transplant patients with various liver diseases and showed that the impact of DSAs on liver damage and rejection was generally limited. Although DSA-positive patients were found to have high MIF values, especially those in diagnostic groups such as Wilson disease and autoimmune hepatitis, no significant association with rejection or liver damage was observed. In addition, DSAs persisting after the first year had no apparent effect on the liver. However, it is important to monitor DSA persistence and titers at certain periods in patients with early positivity after transplantation. It should be taken into account that elevated bilirubin levels in DSA-positive transplant patients may lead to liver damage and seriously threaten graft survival. Therefore, regular pathological examinations and periodic DSA tests during follow-up may be critical for graft survival in these patients. Overall, DSA positivity and immunosuppression therapy were not observed to have a statistically significant impact on rejection, and the results highlight the need for larger-scale studies to understand the effects of DSA on the course of liver transplantation.

5.1 Limitations

This research was a single-center cohort study with retrospective and prospective elements, and the results should be considered preliminary. It is important to recognize that this type of study design may introduce certain biases. In all patients except deceased donors, anti-HLA antibody detection was performed within an average of one year from transplantation, so our estimates of the course of antibody development over time are reliable. However, it is not possible to comment on the immunological status of patients in the following years. As lifestyle factors or treatment adherence during follow-up were not evaluated in our study, we also cannot comment on the effects of these variables on clinical outcomes and DSA formation. In subsequent studies, the individual characteristics, immunological profiles, and clinical conditions of the patients before and after transplantation will be analyzed in more depth. Characteristics such as DSA type, binding ability, titer, and complement binding capacity are planned to be characterized in detail. This will enable the determination of the most appropriate treatment approaches for each patient.

Future research should focus on the development of individualized treatment plans to prevent complications, increase survival rates, and improve the quality of life in patients who develop DSA.

Acknowledgments

The authors are grateful for the reviewer’s valuable comments that improved the manuscript.

  1. Funding information: This article was supported by the Scientific Research Projects Unit of Atatürk University.

  2. Author contributions: Conceptualization, writing – original draft preparation: N. A. and E. B.; data curation: N. A., E. B., and M. K.; validation: E. B.; visualization: N. A., E. B., and M. K.; writing – review and editing: E. B.; investigation: N. A., E. B., M. K., and G. Ö.; material: N. A., G. Ö., S. K., N. A., H. D., and E. D.; methodology: E. B., N. A., and M. K.; supervision: N. A., G. Ö., N. A., S. K., E. K., H. D., and E. D.; resources: N. A., G. Ö., N. A., S. K., E. K., H. D., and E. D. All authors have read and approved the published version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2024-10-16
Revised: 2025-01-17
Accepted: 2025-02-11
Published Online: 2025-03-22

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

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  3. Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
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https://doi.org/10.1515/biol-2025-1078
Schlagwörter für diesen Artikel
liver transplant immunology; donor-specific antibodies; graft rejection mechanisns; chronic allograft dysfunction; molecular biomarkers in transplantation
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Biomedical Sciences
  2. Mechanism of triptolide regulating proliferation and apoptosis of hepatoma cells by inhibiting JAK/STAT pathway
  3. Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
  4. Comparative analysis of inflammatory biomarkers for the diagnosis of neonatal sepsis: IL-6, IL-8, SAA, CRP, and PCT
  5. Post-pandemic insights on COVID-19 and premature ovarian insufficiency
  6. Proteome differences of dental stem cells between permanent and deciduous teeth by data-independent acquisition proteomics
  7. Optimizing a modified cetyltrimethylammonium bromide protocol for fungal DNA extraction: Insights from multilocus gene amplification
  8. Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway
  9. Efficacy of alginate-coated gold nanoparticles against antibiotics-resistant Staphylococcus and Streptococcus pathogens of acne origins
  10. Battling COVID-19 leveraging nanobiotechnology: Gold and silver nanoparticle–B-escin conjugates as SARS-CoV-2 inhibitors
  11. Neurodegenerative diseases and neuroinflammation-induced apoptosis
  12. Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke
  13. COLEC10: A potential tumor suppressor and prognostic biomarker in hepatocellular carcinoma through modulation of EMT and PI3K-AKT pathways
  14. High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway
  15. SIK1 inhibits IL-1β-stimulated cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling
  16. Rutin–chitooligosaccharide complex: Comprehensive evaluation of its anti-inflammatory and analgesic properties in vitro and in vivo
  17. Knockdown of Aurora kinase B alleviates high glucose-triggered trophoblast cells damage and inflammation during gestational diabetes
  18. Calcium-sensing receptors promoted Homer1 expression and osteogenic differentiation in bone marrow mesenchymal stem cells
  19. ABI3BP can inhibit the proliferation, invasion, and epithelial–mesenchymal transition of non-small-cell lung cancer cells
  20. Changes in blood glucose and metabolism in hyperuricemia mice
  21. Rapid detection of the GJB2 c.235delC mutation based on CRISPR-Cas13a combined with lateral flow dipstick
  22. IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts
  23. Short-chain fatty acid attenuates intestinal inflammation by regulation of gut microbial composition in antibiotic-associated diarrhea
  24. Application of metagenomic next-generation sequencing in the diagnosis of pathogens in patients with diabetes complicated by community-acquired pneumonia
  25. NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation
  26. Phytol-mixed micelles alleviate dexamethasone-induced osteoporosis in zebrafish: Activation of the MMP3–OPN–MAPK pathway-mediating bone remodeling
  27. Association between TGF-β1 and β-catenin expression in the vaginal wall of patients with pelvic organ prolapse
  28. Primary pleomorphic liposarcoma involving bilateral ovaries: Case report and literature review
  29. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
  30. Sleep architecture in Alzheimer’s disease continuum: The deep sleep question
  31. Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
  32. Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
  33. Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
  34. Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
  35. Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
  36. Research progress on fecal microbiota transplantation in tumor prevention and treatment
  37. Low-pressure exposure influences the development of HAPE
  38. Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
  39. AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
  40. Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
  41. A case of bloodstream infection caused by Neisseria gonorrhoeae
  42. Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
  43. p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
  44. GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
  45. Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
  46. RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
  47. Decreased serum TIMP4 levels in patients with rheumatoid arthritis
  48. Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
  49. Sodium butyrate aids brain injury repair in neonatal rats
  50. Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
  51. Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
  52. The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
  53. Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
  54. Small cell lung cancer with small intestinal metastasis: Case report and literature review
  55. GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
  56. 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
  57. FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
  58. Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
  59. Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
  60. Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
  61. Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
  62. Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
  63. Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
  64. Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
  65. Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
  66. Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
  67. Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
  68. Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
  69. CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
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  73. Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
  74. Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
  75. Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
  76. Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
  77. The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
  78. Evaluation and application analysis of animal models of PIPNP based on data mining
  79. Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
  80. Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
  81. Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
  82. Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
  83. The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
  84. Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
  85. BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
  86. Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
  87. Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
  88. Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
  89. RNF144A and RNF144B: Important molecules for health
  90. Analysis of the detection rate and related factors of thyroid nodules in the healthy population
  91. Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
  92. Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
  93. Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
  94. SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
  95. Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
  96. Understanding risk factors and prognosis in diabetic foot ulcers
  97. Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
  98. FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
  99. Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
  100. Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
  101. Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
  102. Pulmonary cryptococcosis with headache as the first presentation: A case report
  103. Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
  104. RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
  105. Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
  106. The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
  107. Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
  108. A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
  109. Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
  110. Wound healing and signaling pathways
  111. Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
  112. To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
  113. Research progress on the impact of curcumin on immune responses in breast cancer
  114. Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
  115. Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
  116. Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
  117. ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
  118. Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
  119. Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
  120. Ecology and Environmental Science
  121. Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
  122. The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
  123. Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
  124. Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
  125. Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
  126. Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
  127. Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
  128. Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
  129. Agriculture
  130. Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
  131. Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
  132. Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
  133. Animal Science
  134. Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
  135. Plant Sciences
  136. Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
  137. Widely targeted metabolomics of different tissues in Rubus corchorifolius
  138. The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
  139. Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
  140. Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
  141. Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
  142. Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
  143. Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
  144. Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
  145. The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
  146. Food Science
  147. Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
  148. Review on role of honey in disease prevention and treatment through modulation of biological activities
  149. Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
  150. Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
  151. Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
  152. Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
  153. Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
  154. Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
  155. Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
  156. Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
  157. The dilemma of food genetics and improvement
  158. Bioengineering and Biotechnology
  159. Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
  160. Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
  161. Application of CRISPR/Cas gene editing for infectious disease control in poultry
  162. Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
  163. Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
  164. Corrigendum
  165. Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
  166. Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
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© 2025 De Gruyter Brill
Heruntergeladen am 1.10.2025 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2025-1078/html
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