Search Results (299)

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

Antibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2 cplx) leads to the selective expansion of regulatory T cells (Tregs) and the prolonged survival of MHC-mismatched skin allografts. Although the grafts were eventually rejected, mice failed to develop DSAs. Here, we investigated the impact of IL-2 cplx on the humoral response and germinal center (GC) reaction during allograft rejection. IL-2 cplx treatment prevents Bcl-6 upregulation, leading to suppressed development of GC T and B cells. The IL-2 cplx-induced impairment of GC development limits IgG allo-Ab production but allows for IgM synthesis. By employing a hapten–carrier system to investigate affinity maturation, we found that IL-2 cplx induces a distinct shift in specific Ab production favoring low-affinity IgM while simultaneously decreasing IgG responses. These findings illuminate the potential of IL-2 cplx therapy for inducing humoral tolerance, potentially paving the way for refining strategies aimed at preventing and treating ABMR. Full article

Although transplantation remains the gold-standard treatment for patients with end-organ failure, lifelong adherence to immunosuppressant medication is required to prevent rejection, graft failure, and mortality. Given the increase in thoracic organ transplantation, it is crucial to better understand the associated barriers to treatment. Examining sociodemographic, transplant, healthcare access, post-transplant treatment, and patient-related psychosocial factors may help to elucidate treatment barriers that have not been previously considered in the existing literature. This single-site cross-sectional study surveyed 65 thoracic (heart and lung) transplant recipients (mean age: 62 years; 76.2% male; 72.3% White, and 21.5% Black) via phone interviews. Immunosuppressant nonadherence was found in 49.2% of participants (46.9% heart, 51.5% lung). In a four-week period, 20% of participants missed at least one dose, 40% did not take their medications on time, and 1% stopped completely. Significant correlates of nonadherence included poorer diet quality, fewer comorbidities, and maladaptive coping responses to perceived discrimination. This preliminary study highlights the importance of considering the social determinants of health—particularly post-transplant treatment and psychosocial patient-related factors—to inform post-transplant care. Addressing such variables may improve medication adherence and, subsequently, overall health outcomes. Further research with larger samples is needed to better understand the associated correlates and inform effective interventions for enhanced medication adherence. Full article

Background: Donor-derived cell-free DNA (dd-cfDNA) testing offers a non-invasive approach for monitoring allograft health in transplant recipients. However, its diagnostic performance and clinical utility remain insufficiently characterized across diverse populations. Objectives: This study assesses concordance between dd-cfDNA, donor-specific antibody (DSA) testing, and biopsy, while also comparing two commercial assays (AlloSure and Prospera) in kidney and pancreas transplant recipients. Methods: We retrospectively analyzed 271 transplant patient records from 2019 to 2024 at our institution, focusing on dd-cfDNA testing. Statistical analyses evaluated assay performance in relation to DSA and biopsy results. The impact of multi-organ transplantation (MOT) on dd-cfDNA levels was also assessed. Results: In our predominantly Caucasian cohort (61.5%) with a mean age of 53 years, increased levels of dd-cfDNA were significantly associated with DSA positivity, particularly within the Prospera group (p = 0.002), and were particularly higher in patients with HLA class II DSA. Both assays showed a limited correlation with biopsy-confirmed rejection. AlloSure had high specificity (80%) but low sensitivity (19%), whereas Prospera showed higher sensitivity (75%) with moderate specificity (60%). Dd-cfDNA levels were elevated in MOT recipients in a vendor-dependent manner. Conclusions: Our findings highlight the differing clinical strengths of dd-cfDNA assays: AlloSure demonstrates greater preference for ruling out rejection, whereas Prospera appears better suited for early detection. Dd-cfDNA interpretation in MOT recipients warrants cautious consideration. Overall, tailoring assay selection and optimizing diagnostic thresholds to clinical context may enhance transplant surveillance and patient management strategies. Full article

Liver transplantation faces significant challenges, primarily due to the severe shortage of organs—aggravated by the increasing prevalence of liver diseases—and graft loss due to the consequences of ischemia/reperfusion injury (I/RI) and rejection. A recent study highlights the critical role of autophagy, a cellular breakdown and recycling mechanism, in addressing these issues. This article examines the role of autophagy in liver transplantation, focusing on organ preservation and recovery after surgery, as well as its potential to regulate immune responses and increase graft survival. Additionally, it will cover the role of autophagy in xenotransplantation, a prospective solution to the organ scarcity crisis. Ultimately, it assesses the importance of precisely timing autophagy modulation—whether induction or inhibition—to enhance transplantation outcomes, while identifying key knowledge gaps and future research directions. Full article

Background/Objectives: Donation after circulatory death (DCD) has emerged to expand the heart-donor pool, but many DCD donors have risk factors such as cocaine or methamphetamine use. Stimulant use can cause coronary vasospasm and premature coronary artery disease, leading to routine donor coronary angiography (left heart catheterization, LHC) for coronary screening. However, performing LHC in DCD donors is challenging. We examined whether omitting LHC in stimulant-exposed DCD donors affects outcomes. Methods: A retrospective analysis was performed using the United Network for Organ Sharing (UNOS) database (2019–2024) to identify adult heart transplant recipients from DCD donors with documented cocaine or amphetamine use. Donors were stratified by whether antemortem LHC was performed. The primary outcome was 1-year recipient survival; secondary outcomes included graft failure and acute rejection. Kaplan–Meier survival curves and Cox regression analyses were performed. Results: A total of 485 DCD heart transplant recipients were identified; 135 (28%) donors underwent LHC and 350 (72%) did not. Recipient characteristics were similar between groups. No significant differences in 30-day (6% vs. 3%; p = 0.11), 90-day (6% vs. 3%; p = 0.21), or 1-year survival (7% vs. 6%; p = 0.48) were observed between the LHC and non-LHC cohorts. Graft failure and complication rates were also similar. However, among stimulant-exposed DCD donors with diabetes, an absence of LHC was associated with higher recipient mortality (HR 5.86, 95% CI: 1.57–21.87; p = 0.008). Conclusions: Routine donor coronary angiography may be unnecessary for stimulant-exposed DCD donors without additional risk factors. Omitting LHC did not compromise transplant outcomes. A selective LHC approach for high-risk DCD donors (e.g., diabetic donors) could safely expand the donor pool. Full article

Background/Objectives: Tacrolimus is an immunosuppressant drug widely used to prevent organ transplant rejection. Preclinical and clinical studies report that tacrolimus has destructive impacts on the male reproductive system owing to the induction of oxidative stress and inflammation. This study aimed at examining defensive impacts of agmatine against tacrolimus-induced testicular toxicity in rats. Methods: Male Wistar rats were randomly divided into six groups and treated based on the experimental design for 14 days. By the end of this study, blood samples were obtained to measure testosterone and luteinizing hormone. Also, both testes were removed for molecular analysis and histopathological examinations. Results: Agmatine administration increased serum levels of testosterone and luteinizing hormone and ameliorated all histopathological and toxicological changes induced by tacrolimus. Agmatine administration attenuated tacrolimus-induced oxidative stress as evidenced by the reduction of malondialdehyde content and inducible nitric oxide synthase expression and the elevation of reduced glutathione. This was parallel to the restoration of nuclear factor erythroid 2-related factor2 and hemeoxygenase-1 expression. Moreover, agmatine decreased the expressions of nuclear factor kappa B and interleukin-17. Agmatine also decreased the cell death revealed by decreased caspase-3 expression and increased expression of the antiapoptotic marker Bcl-2 in a dose-dependent manner. The antioxidant, anti-inflammatory, and antiapoptotic effects of agmatine were explained by increased expression of sirtuin-1. Conclusions: agmatine effectively attenuated testicular injuries induced by tacrolimus and enhanced spermatogenesis. This protective effect of agmatine might be mediated via the upregulation of sirtuin-1 expression that in turn restores oxidative status and regulates nuclear factor erythroid 2-related factor2/nuclear factor kappa B/Bcl-2 signaling. Full article

Effective immunosuppressant pharmacotherapy is essential for successful organ transplantation. Background/Objectives: Generally, induction therapy includes basiliximab (BAS) or anti-thymocyte globulin (THY). However, other biological molecules have been used to accelerate firm immunosuppression. A reduced effectiveness of these induction agents increases the risk of graft rejection. This study aims to evaluate the ineffectiveness rate of biological molecules based on spontaneous reports uploaded to the EudraVigilance database. Methods: Specific topics related to the safety profiles of alemtuzumab, BAS, belatacept, and THY were analyzed. A total of 23 preferred terms describing drug resistance, drug ineffectiveness, and transplant rejection were used as the inclusion criteria. Descriptive and disproportionality analyses were performed. Results: Regarding the four molecules, 18,564 safety reports were communicated, with n = 5089 (27.4%) for THY and n = 3469 (18.7%) for BAS. Most adverse drug reactions (ADRs) for THY, BAS, and belatacept affected the adult male population. As expected, the majority of the ADRs were linked to infections, followed by general disorders. BAS presented higher probabilities of drug resistance and transplant rejection being reported among the four molecules. A higher probability of reporting drug ineffectiveness was noted for THY than for the other molecules. Conclusions: All the molecules showed small frequencies regarding resistance. As expected, transplant rejection was more frequently reported for all molecules (especially for BAS), accompanied by a notable variability in reporting frequencies. However, a causal relationship between the reported adverse reactions and drug efficacy cannot be established based on the present results. Further real-world evidence studies will enhance our understanding of the safety and efficacy of these drugs in transplant patients. Full article

Purpose: The success of solid organ transplantation and the consequent increase in the patients on the waiting list has led to an increased utilization of donor kidneys with a high kidney donor profile index (KDPI)/expanded criteria. In our study, patients who underwent transplantation based on the standard and expanded donor criteria were compared in terms of factors affecting graft survival. Data of patients who underwent transplantation from cadavers with standard and extended criteria (SCD, ECD) between 01 July 2011 and 30 June 2016 were evaluated retrospectively. Donor characteristics, treatment type, response and graft characteristics, 1st-, 3rd-, and 5th-year graft survival, and acute rejection rates were analyzed retrospectively. Recent findings: In terms of the causes of death, cerebrovascular accidents were more common in the ECD group (p < 0.001). Hypertension and diabetes were more common in both donor groups and were detected more frequently in recipients in the ECD group (p < 0.001). The absence of mycophenolate mofetil (MMF) use and the presence of an acute rejection attack adversely affected graft survival at the end of the 1st, 3rd, and 5th years. Summary: The utilization of expanded criteria donors is widespread. Appropriate monitoring of patients undergoing immunosuppressive therapy, especially using mycophenolate mofetil (MMF) and the presence of acute rejection, affect graft survival. Full article

Background and Clinical Significance: Post-transplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation, often associated with prolonged immunosuppression. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype. Managing PTLD requires a balance between reducing immunosuppression and preventing graft rejection. Case Presentation: A 41-year-old female kidney transplant recipient developed PTLD eight years post-transplant, presenting with a right submandibular mass. Biopsy confirmed CD20-positive DLBCL. Initial treatment involved reducing immunosuppression and rituximab monotherapy, which failed to prevent disease progression. The patient underwent six cycles of R-CHOP chemotherapy, achieving complete metabolic remission. Relapse occurred twice, with disease progression in the cervical nodes and tonsils. Salvage therapies, including polatuzumab vedotin and rituximab, achieved remission. During a subsequent relapse, loncastuximab tesirine induced metabolic resolution. Compromised renal function limited treatment options and a second renal transplant was delayed, reducing the risk of PTLD recurrence. Conclusions: This case underscores the challenges of managing PTLD in transplant recipients, especially in relapsed/refractory cases. Single-agent rituximab was insufficient, but combination chemotherapy and novel agents like loncastuximab tesirine were effective. Balancing oncologic control and graft preservation remains critical. This case highlights the need for individualized approaches and novel therapies in managing PTLD while addressing the complexities of immunosuppression and organ preservation. Full article

Heart transplantation remains the gold-standard treatment for end-stage heart failure, yet long-term graft survival is hindered by chronic rejection and the morbidity and mortality caused by lifelong immunosuppression. While advances in medical and device-based therapies have reduced the overall need for transplantation, patients who ultimately require a transplant often present with more advanced disease and comorbidities. Recent advances in tolerance-inducing strategies offer promising avenues to improve allograft acceptance, while minimizing immunosuppressive toxicity. This review explores novel approaches aiming to achieve long-term immunological tolerance, including co-stimulation blockade, mixed chimerism, regulatory T-cell (Treg) therapies, thymic transplantation, and double-organ transplantation. These strategies seek to promote donor-specific unresponsiveness and mitigate chronic rejection. Additionally, expanding the donor pool remains a critical challenge in addressing organ shortages. Innovations such as ABO-incompatible heart transplantation are revolutionizing the field by increasing donor availability and accessibility. In this article, we discuss the mechanistic basis, clinical advancements, and challenges of these approaches, highlighting their potential to transform the future of heart transplantation with emphasis on clinical translation. Full article

Background: Heart transplantation (Htx) remains the definitive therapy for patients with end-stage heart failure. Despite advancements in mechanical circulatory support (MCS), immunosuppressive strategies, and organ allocation policies, donor availability remains a major limitation. This study analyzes the trends in Htx in the United States between 2016 and 2022, focusing on demographic shifts, mortality trends, and 30-day readmission patterns. Methods: We utilized the National Inpatient Sample (NIS) from 2016 to 2022 and the National Readmissions Database (NRD) for 2021 to identify Htx admissions using ICD-10 PCS code O2YA0Z0. Patient characteristics, mortality rates, and readmission patterns were analyzed using ANOVA and multivariate logistic regression, with statistical significance defined as p < 0.05. Results: The total number of Htx procedures increased from 641 in 2016 to 773 in 2022. The mean age of transplant recipients remained between 45 and 50 years, with no significant differences across years. Racial and socioeconomic disparities persisted, with approximately 60% of transplants occurring in White patients and 21–26% of recipients belonging to the lowest income quartile. All-cause in-hospital mortality remained stable at 4–7%. The 30-day readmission rate in 2021 was 57.7%, with heart failure, transplant rejection, and infections being the leading causes. Peripheral vascular disease (PVD) was the only comorbidity significantly associated with higher 30-day readmission risk (OR: 1.815, 95% CI: 1.477–2.230). Conclusions: Htx utilization has increased over time, driven by improvements in donor allocation and perioperative management. However, racial and socioeconomic disparities remain, and readmission rates continue to be high. Future efforts should focus on optimizing post-transplant care and addressing disparities to improve long-term outcomes. Full article

The complex nature of immune system behavior in both autoimmune diseases and transplant rejection can be understood through the lens of avalanche dynamics in critical-point systems. This paper introduces the concept of the “immunological avalanche” as a framework for understanding unpredictable patterns of immune activity in both contexts. Just as avalanches represent sudden releases of accumulated potential energy, immune responses exhibit periods of apparent stability followed by explosive flares triggered by seemingly minor stimuli. The model presented here draws parallels between immune system behavior and other complex systems such as earthquakes, forest fires, and neuronal activity, where localized events can propagate into large-scale disruptions. In autoimmune conditions like systemic lupus erythematosus (SLE), which affects multiple organ systems including the kidneys in approximately 50% of patients, these dynamics manifest as alternating periods of remission and flares. Similarly, in transplant recipients, the immune system exhibits metastable behavior under constant allograft stimulation. This critical-point dynamics framework is characterized by threshold-dependent activation, positive feedback loops, and dynamic non-linearity. In autoimmune diseases, triggers such as UV light exposure, infections, or stress can initiate cascading immune responses. In transplant patients, longitudinal analysis reveals how monitoring oscillatory patterns in blood parameters and biological age markers can predict rejection risk. In a preliminary study on kidney transplant, all measured variables showed temporal instability. Proteinuria exhibited precise log–log linearity in power law analysis, confirming near-critical-point system behavior. Two distinct dynamic patterns emerged: large oscillations in eGFR, proteinuria, or biological age predicted declining function, while small oscillations indicated stability. During avalanche events, biological age increased dramatically, with partial reversal leaving persistent elevation after acute episodes. Understanding these dynamics has important implications for therapeutic approaches in both contexts. Key findings suggest that monitoring parameter oscillations, rather than absolute values, better indicates system instability and potential avalanche events. Additionally, biological age calculations provide valuable prognostic information, while proteinuria measurements offer efficient sampling for system dynamics assessment. This conceptual model provides a unifying framework for understanding the pathogenesis of both autoimmune and transplant-related immune responses, potentially leading to new perspectives in disease management and rejection prediction. Full article

Background/Objectives: Solid organ transplantation remains a critical life-saving treatment for end-stage organ failure, yet it faces persistent challenges, such as organ scarcity, graft rejection, and postoperative complications. Artificial intelligence (AI) has the potential to address these challenges by revolutionizing transplantation practices. Methods: This review article explores the diverse applications of AI in solid organ transplantation, focusing on its impact on diagnostics, treatment, and the evolving market landscape. We discuss how machine learning, deep learning, and generative AI are harnessing vast datasets to predict transplant outcomes, personalized immunosuppressive regimens, and optimize patient selection. Additionally, we examine the ethical implications of AI in transplantation and highlight promising AI-driven innovations nearing FDA evaluation. Results: AI improves organ allocation processes, refines predictions for transplant outcomes, and enables tailored immunosuppressive regimens. These advancements contribute to better patient selection and enhance overall transplant success rates. Conclusions: By bridging the gap in organ availability and improving long-term transplant success, AI holds promise to significantly advance the field of solid organ transplantation. Full article