Human leukocyte antigen and donor-specific antibodies in liver transplantation

Abstract

In this article, we comment on an article published in a recent issue of the World Journal of Gastroenterology. We specifically focus on the roles of human leukocyte antigen (HLA) and donor-specific antibodies (DSAs) in pediatric liver transplantation (LT), as well as the relationship between immune rejection after LT and DSA. Currently, LT remains the standard of care for pediatric patients with end-stage liver disease or severe acute liver failure. However, acute and chronic rejection continues to be a significant cause of graft dysfunction and loss. HLA mismatch significantly reduces graft survival and increases the risk of acute rejection. Among them, D→R one-way mismatch at three loci was significantly related to graft-versus-host disease incidence after LT. The adverse impact of HLA-DSAs on LT recipients is already established. Therefore, the evaluation of HLA and DSA is crucial in pediatric LT.

Key Words: Liver transplantation; Human leukocyte antigen; Donor-specific antibodies; De novo donor-specific antibody; Antibody-mediated rejection

Core Tip: Donor-specific antibodies (DSAs), particularly those against human leukocyte antigen (HLA) DQ loci, significantly affect rejection risk and graft survival in pediatric liver transplantation. The presence of DSAs is linked to increased rates of both acute and chronic rejection, which impacts long-term graft viability. These findings highlight the importance of improved HLA and DSA monitoring and management to improve long-term outcomes in pediatric liver transplant recipients.

TO THE EDITOR

The human major histocompatibility complex is a family of genes that encode human leukocyte antigens (HLAs), vital for immunological surveillance of malignancies and resistance against external infections. HLA molecules are polymorphic antigens that constitute an immunodominant alloreactive trigger for the immune response, leading to rejection following transplantation[1]. In organ transplantation, HLA matching offers several advantages, such as improved graft function, fewer rejection events, extended graft life, and the potential for less immunosuppression. More frequent episodes of rejection accompanying mismatches necessitate heightened immunosuppression, raising the risk of infection and cancer[2]. Donor-specific antibody (DSA) has emerged as an essential biomarker of allograft injury[3]. These antibodies bind to donor HLA molecules, leading to graft damage. DSA can be categorized into preformed DSAs, which develop prior to transplantation due to previous exposure to non-self HLAs, and de novo DSA (dn-DSAs), which form post-transplantation response to the donor's HLA[4]. Preformed DSAs reflect alloimmune memory, while dn-DSAs indicate a primary immune response[5]. Studies have shown that preformed DSAs increase the risk of acute rejection and reduce graft survival, which is why they are frequently regarded as a transplant contraindication. Additionally, dn-DSA is linked to an increased risk of rejection, chronic or acute antibody-mediated rejection (AMR), and most likely mixed rejection[6]. According to a meta-analysis, there was acceptable heterogeneity and no discernible publication bias in the high correlation between dn-DSA and increased liver transplantation (LT) rejection risk. In the long-term follow-up, the rejection rates for dn-DSA-positive patients were almost seven times greater than those for dn-DSA-negative individuals. Additionally, dn-DSAs continued to significantly impact allograft outcomes in pediatric LT patients, increasing these patients by around ten times compared to patients with negative dn-DSA[7]. Moreover, DSA is associated with long-term allograft fibrosis after LT[6]. Therefore, progressive fibrosis after LT in pediatric recipients may reflect ongoing silent AMR. In particular, patients who do not take the medications as prescribed, have consistently low immunosuppression levels, or are candidates for immunosuppression withdrawal. Regular liver tests in the presence of progressive inflammation and fibrosis may suggest the need for protocol liver biopsies in addition to routine DSA and C4d analysis. The laxity of chronic AMR may obscure its actual effect on allograft health despite acutely increased prominence of AMR due to its evident and abrupt path to allograft failure. Chronic AMR fibrosis can lead to allograft cirrhosis, and many of these individuals may eventually develop concurrent chronic ductopenic rejection. The possibility of fibrosis reversibility with an increase in immunosuppression is unknown[8].

HLA and DSA in LT

As part of the immune recognition process, which is essential to the adaptive immune response, HLAs, which are cell surface proteins, present peptides to T cells, with thousands of alleles identified for the HLA loci, the HLA genes are the most polymorphic in the human genome[9]. HLA mismatches play a significant role in LT. This retrospective observational analysis included 22702 liver transplant recipients from the large-scale multi-center database UNOS/OPTN. Patients were divided into two groups according to the number of HLA mismatches (0–3 vs 4–6 mismatches), and the results were further subdivided by donor status and indication. The degree of HLA mismatch was linked to both the risk of acute rejection and allograft survival, and this relationship remained in patients who received transplants for congenital indications, metabolic disorders, hepatitis, and medications[10]. These findings underscore the importance of HLA matching in LT, suggesting that minimizing mismatches could improve graft longevity and reduce rejection risks across diverse patient groups.

Sensitization, the presence of anti-HLA antibodies, develops after exposure to non-self HLA through pregnancy, blood transfusion, or a previous organ transplant. Anti-HLA antibodies against the allograft can bring on both early AMR, which can occur days to weeks after transplantation, and hyperacute rejection, which can occur within minutes to hours of reperfusion. Allograft malfunction and failure may result from these types of rejection[9]. For a long time, the liver was thought to be less vulnerable to AMR than other organs. However, research has shown that anti-HLA antibodies, particularly DSAs, are essential for graft survival during pediatric LT[11]. Children are more likely than adults to experience DSAs following LT. DSAs target HLA class II molecules more frequently, primarily DQ. Such anti-class II DSAs (DQ/DR), particularly those of the complement-binding IgG3 subclass, may be linked to fibrosis, inflammation, endothelial damage, and T-cell-mediated rejection[12]. In the study by Melere et al[13], 67 transplanted youngsters were examined; 61 received grafts from living donors, and 85% were related to the recipients. Of these patients, 28.3% had pre-transplant DSA (class I or II) and 48.4% had dn-DSA. Patients with and without dn-DSA anti-DQ had rejection-free survival rates of 76% vs 100% and 58% vs 95% at 12 and 24 months, respectively. Consequently, the results emphasize the importance of including DSA evaluation in protocols for pediatric LT recipients both before and after transplantation. Based on this analysis in pediatric LT recipients, future implications may include immunosuppression minimization strategies. Liu et al[14] showed that DSAs against HLA class II antigens accounted for 90% of all DSAs and were more prevalent than those against class I antigens in a retrospective cohort analysis including 48 juvenile liver transplant recipients. The HLA-DQ site dominates the HLA-II antigen. In the study by Miyagawa-Hayashino et al[15] 79 pediatric patients with satisfactory graft function who had a protocol liver biopsy performed more than five years following transplantation (median = 11 years, range = 5-20 years) were the subjects of a retrospective analysis. The findings demonstrated that 67 patients had DSAs: 32 patients (48%) had DSAs identified; these were often against HLA class II (30 cases), but were infrequently against class I (2 cases). Bridging fibrosis or cirrhosis was more common in these individuals (28/32 or 88%) than in DSA-negative patients (6/35 or 17%, P < 0.001). The study demonstrated that the presence of DSAs in pediatric patients more than 5 years post-transplant is associated with a higher incidence of fibrosis or cirrhosis, suggesting that DSAs may serve as an essential marker for long-term transplant complications.

Improvements in post-transplant survival can essentially be due to more targeted and less toxic immunosuppressive regimens. Liver grafts have been observed to stimulate less rejection compared with other organs. By causing peripheral microchimerism and a degree of tolerance, they may offer protection for other organs transplanted simultaneously. However, immunosuppression is still a barrier to long-term graft survival. Current regimens control various pathways, from calcineurin and mTOR inhibitors to antimetabolites and several antibody treatments, providing a chance to adapt each recipient’s regimen. Targeting distinct immune system pathways also reduces dosage and drug toxicity without raising the risk of neoplasms, opportunistic infections, or rejection[16]. Vionnet et al[17] conducted a cross-sectional multicenter study of 190 adult LT recipients. The findings demonstrated the usefulness of liver stiffness measurement, class II DSAs, and alanine aminotransferase in noninvasively identifying stable LT recipients who may benefit from immunosuppressive minimization but do not have considerable underlying alloimmunity[18]. These tools can help identify stable patients who may not require intense immunosuppression; however, further research is needed to assess their applicability across different populations. Additionally, strict adherence to the treatment plan, lifelong immunosuppressive medication use, and vigilant medical monitoring are critical to long-term results following LT. In children who undergo LT, nonadherence is the most frequent cause of late acute rejection, with an estimated 35% to 50% of adolescents experiencing nonadherence[19].

CONCLUSION

Although AMR after LT has received increasing attention, there is still little information on LT consequences in pediatric patients. Nevertheless, the role of HLA mismatches and DSAs in pediatric LT has been identified as a critical determinant of graft survival and immune rejection. Current studies demonstrate the significant impact of HLA mismatches on acute and chronic rejection, with a strong association between DSAs, particularly those targeting HLA class II, and long-term graft outcomes. While advancements in immunosuppressive regimens have improved post-transplant survival, the presence of DSAs, especially in pediatric populations, continues to pose risks for graft dysfunction and fibrosis. Pre- and post-transplant DSA monitoring is essential for identifying high-risk patients and optimizing immunosuppressive strategies. Future research should prioritize standardizing DSA detection protocols and optimizing immunosuppressive strategies to improve graft survival. Additionally, developing long-term follow-up and management plans, particularly addressing the unique needs of pediatric patients, is critical to ensuring the ongoing health and functionality of the transplanted organ. Despite advances in understanding the impact of DSAs on pediatric LT, continued research is crucial to ensure the long-term success of these procedures.