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Animal models for transplant immunology:bridging bench to bedside

Minseok KANG ; Hwon Kyum PARK ; Kyeong Sik KIM ; Dongho CHOI

Clinical Transplantation and Research.2024;38(4):354-376. doi:10.4285/ctr.24.0029

The progress of transplantation has been propelled forward by animal experiments.Animal models have not only provided opportunities to understand complex immune mechanisms in transplantation but also served as a platform to assess therapeutic interventions. While small animals have been instrumental in uncovering new therapeutic concepts related to immunosuppression and immune tolerance, the progression to human trials has largely been driven by studies in large animals. Recent research has begun to explore the potential of porcine organs to address the shortage of available organs. The consistent progress in transplant immunology research can be attributed to a thorough understanding of animal models. This review provides a comprehensive overview of the available animal models, detailing their modifications, strengths, and weaknesses, as well as their historical applications, to aid researchers in selecting the most suitable model for their specific research needs.

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Belatacept and regulatory T cells in transplantation: synergistic strategies for immune tolerance and graft survival

Gil-Ran KIM ; Kyung-Ho NAM ; Je-Min CHOI

Clinical Transplantation and Research.2024;38(4):326-340. doi:10.4285/ctr.24.0057

Calcineurin inhibitors (CNIs) have been a cornerstone in solid organ transplantation for many years; however, their prolonged use is linked to significant adverse effects, most notably nephrotoxicity. Belatacept, a modified version of cytotoxic T lymphocyte antigen-4 immunoglobulin with increased binding affinity for its ligand, has emerged as a viable alternative to traditional CNIs due to its lower toxicity profile. Despite these benefits, belatacept is associated with a higher rate of acute rejection, which presents a challenge for long-term graft survival. This review reevaluates the limitations of belatacept in achieving long-term acceptance of transplants and highlights the importance of regulatory T (Treg) cells in maintaining immune tolerance and preventing graft rejection. Additionally, it discusses the potential benefits of combining therapies that boost Treg cells with belatacept to increase the effectiveness of immunosuppression and improve graft outcomes.

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A walk through the development of human leukocyte antigen typing: from serologic techniques to next-generation sequencing

Haeyoun CHOI ; Eun-Jeong CHOI ; Hyoung-Jae KIM ; In-Cheol BAEK ; Aegyeong WON ; Su Jin PARK ; Tai-Gyu KIM ; Yeun-Jun CHUNG

Clinical Transplantation and Research.2024;38(4):294-308. doi:10.4285/ctr.24.0055

Human leukocyte antigen (HLA) is a group of glycoproteins encoded by the major his-tocompatibility complex (MHC) that plays a pivotal role in the host's immune defense.Given that the MHC represents the most polymorphic region in the human genome, HLA typing is crucial in organ transplantation. It significantly influences graft rejection, graft-versus-host disease, and the overall patient outcome by mediating the discrimination between self and nonself. HLA typing technology began with serological methods and has evolved rapidly alongside advances in molecular technologies, progressing from DNA-based typing to next- or third-generation sequencing. These advancements have increased the accuracy of HLA typing and reduced ambiguities, leading to marked improvements in transplantation outcomes. Additionally, numerous novel HLA alleles have been identified. In this review, we explore the developmental history and future prospects of HLA typing technology, which promises to further benefit the field of transplantation.

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Mechanisms of allorecognition and xenorecognition in transplantation

Il Hee YUN ; Jaeseok YANG

Clinical Transplantation and Research.2024;38(4):273-293. doi:10.4285/ctr.24.0056

Foreign antigen recognition is the ability of immune cells to distinguish self from nonself, which is crucial for immune responses in both invertebrates and vertebrates. In vertebrates, T cells play a pivotal role in graft rejection by recognizing alloantigens presented by antigen-presenting cells through direct, indirect, or semidirect pathways.B cells also significantly contribute to the indirect presentation of antigens to T cells.Innate immune cells, such as dendritic cells, identify pathogen- or danger-associated molecular patterns through pattern recognition receptors, thereby facilitating effective antigen presentation to T cells. Recent studies have shown that innate immune cells, including macrophages and NK cells, can recognize allogeneic or xenogeneic antigens using immune receptors like CD47 or activating NK receptors, instead of pattern recognition receptors. Additionally, macrophages and NK cells are capable of exhibiting memory responses to alloantigens, although these responses are shorter than those of adaptive memory. T cells also recognize xenoantigens through either direct or indirect presentation. Notably, macrophages and NK cells can directly recognize xenoantigens via surface immune receptors in an antibody-independent manner, or they can be activated in an antibody-dependent manner. Advances in our understanding of the recognition mechanisms of adaptive and innate immunity against allogeneic and xenogeneic antigens may improve our understanding of graft rejection.

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Beyond the icebox: modern strategies in organ preservation for transplantation

Kidus Haile YEMANEBERHAN ; Minseok KANG ; Jun Hwan JANG ; Jin Hee KIM ; Kyeong Sik KIM ; Ho Bum PARK ; Dongho CHOI

Clinical Transplantation and Research.2024;38(4):377-403. doi:10.4285/ctr.24.0039

Organ transplantation, a critical treatment for end-stage organ failure, has witnessed significant advancements due to the integration of improved surgical techniques, immunosuppressive therapies, and donor-recipient matching. This review explores the progress of organ preservation, focusing on the shift from static cold storage (SCS) to advanced machine perfusion techniques such as hypothermic (HMP) and normothermic machine perfusion (NMP). Although SCS has been the standard approach, its limitations in preserving marginal organs and preventing ischemia-reperfusion injury (IRI) have led to the adoption of HMP and NMP. HMP, which is now the gold standard for high-risk donor kidneys, reduces metabolic activity and improves posttransplant outcomes. NMP allows real-time organ viability assessment and reconditioning, especially for liver transplants. Controlled oxygenated rewarming further minimizes IRI by addressing mitochondrial dysfunction. The review also highlights the potential of cryopreservation for long-term organ storage, despite challenges with ice formation. These advances are crucial for expanding the donor pool, improving transplant success rates, and addressing organ shortages. Continued innovation is necessary to meet the growing demands of transplantation and save more lives.

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Targeting T helper 17 cells: emerging strategies for overcoming transplant rejection

Young Joon LEE ; Mi-La CHO

Clinical Transplantation and Research.2024;38(4):309-325. doi:10.4285/ctr.24.0058

Solid organ transplantation has significantly improved the survival rate of patients with terminal organ failure. However, its success is often compromised by allograft rejection, a process in which T helper 17 (Th17) cells play a crucial role. These cells facilitate rejection by enhancing neutrophil infiltration into the graft and by activating endothelial cells and fibroblasts. Additionally, Th17 cells can trigger the activation of other T cell types, including Th1, Th2, and CD8+ T cells, further contributing to rejection. An imbalance between Th17 and regulatory T cells (Tregs) is known to promote rejection. To counteract this, immunosuppressive drugs have been developed to inhibit T cell activity and foster transplant tolerance. Another approach involves the adoptive transfer of regulatory cells, such as Tregs and myeloid-derived suppressor cells, to dampen T cell functions. This review primarily focuses on the roles of Th17 cells in rejection and their interactions with other T cell subsets. We also explore various strategies aimed at suppressing T cells to induce tolerance.

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Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance

Ji Won HAN ; Su-Hyung PARK

Clinical Transplantation and Research.2024;38(4):257-272. doi:10.4285/ctr.24.0059

Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver’s distinct immunological microenvironment, characterized by tolerogenic antigen-presentingcells and high levels of interleukin (IL)-10 and transforming growth factor-β, positionsthis organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.

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SARS-CoV-2 vaccine-elicited immune responses in solid organ transplant recipients

Euri SEO ; Eui-Cheol SHIN ; Min Kyung JUNG

Clinical Transplantation and Research.2024;38(4):247-256. doi:10.4285/ctr.24.0062

Solid organ transplant recipients (SOTRs) are considered a high-risk group for coronavirus disease 2019 (COVID-19). The adaptive immune responses generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination include humoral and cellular immune responses. Most studies on the SARS-CoV-2 vaccine have focused primarily on humoral immunity, but cellular immunity is vital for effectively controlling progression to severe COVID-19. In SOTRs, the vaccine-induced adaptive immune response is significantly attenuated compared to the response in healthy individuals.Nevertheless, vaccinated SOTRs exhibit a reduced rate and severity of SARS-CoV-2 infection. This review aims to provide a concise overview of the current understanding of SARS-CoV-2 vaccine-induced immune responses in SOTRs.

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Contribution of long-lived plasma cells to antibody-mediated allograft rejection

Eunkyeong JANG ; Jeehee YOUN

Clinical Transplantation and Research.2024;38(4):341-353. doi:10.4285/ctr.24.0047

Persistent alloantigens derived from allograft tissues can be recognized by the host’s alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers.However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.

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Kaposi sarcoma of a liver graft in living donor liver transplantation: a rare case report

Umid SALIMOV ; Palat BALACHANDRAN ; Konstantin SEMASH

Clinical Transplantation and Research.2025;39(1):77-83. doi:10.4285/ctr.24.0030

Kaposi sarcoma following solid organ transplantation is a rare and underreported complication, with few cases documented globally concerning its origin from liver grafts.This case report describes an Asian woman who developed Kaposi sarcoma in a liver graft following living donor liver transplantation for end-stage liver disease resulting from hepatitis D virus. In accordance with current guidelines, standard immunosuppression was discontinued, and mammalian target of rapamycin (mTOR) inhibitors were initiated. The use of mTOR inhibitors led to the complete resolution of the liver graft lesions within 9 months. However, subsequent follow-up revealed several complications, including late anastomotic biliary stricture, extensively drug-resistant Klebsiella pneumoniae infection, and subtotal hydrothorax. These complications required intensive care unit admission, biliary stenting, oxygen therapy, and pleural drainage. Despite the severity of her condition, the patient fully recovered and showed no signs of recurrence throughout the 64-month follow-up period. To our knowledge, this is the first reported case of Kaposi sarcoma in a liver graft with such an extended follow-up.

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