Transplantation Direct最新文献

Background: Long-term outcomes in kidney transplantation remain suboptimal, with subclinical acute rejection (subAR) frequently going undetected by conventional methods. We hypothesized that subAR represents a molecular precursor to clinical acute rejection (cAR). Leveraging a large National Institutes of Health-funded cohort with matched kidney tissue and peripheral blood samples, our primary objective was to determine whether subAR and cAR share molecular patterns, establishing subAR as an early stage of cAR. As a secondary aim, we compared biopsy and blood gene expression profiles to identify unique and shared pathways and to assess their diagnostic utility.

Methods: This was a retrospective analysis of gene expression data from an observational clinical trial. We analyzed 578 blood and biopsy samples from 129 kidney transplant recipients enrolled in a multicenter observational study. Gene expression differences were analyzed using ANOVA with false discovery rate correction and molecular pathways analysis. Samples were matched and classified based on histologic findings and blood-based molecular diagnostics.

Results: Gene expression and pathway analyses revealed that subAR exhibits a molecular profile consistent with a milder form of clinical rejection in both tissue and blood. Molecular signatures distinguished immune-mediated injury from nonimmune injury. Notably, tissue gene expression profiling in cases that were misclassified by peripheral blood diagnostics were like correctly classified cases, suggesting that histology alone may not reliably define true clinical phenotypes.

Conclusions: Molecular profiling of tissue and blood reflects distinct but complementary aspects of transplant biology and confirms that subAR and cAR share overlapping molecular profiles, supporting the hypothesis that subAR represents an early stage in the progression toward clinical rejection. These findings highlight the limitations of relying solely on histological evaluation and support the use of molecular tissue profiling as an adjunct to histology, particularly in diagnostically ambiguous cases. Molecular profiling provides a supporting framework for identifying subclinical rejection and guiding personalized immunosuppression to improve long-term outcomes.

[This corrects the article DOI: 10.1097/TXD.0000000000001862.].

[This corrects the article DOI: 10.1097/TXD.0000000000001829.].

Background: Globally, deceased donor kidney allocation algorithms prioritize HLA matching, potentially disadvantaging transplant candidates with less common HLA alleles. This study developed an Australian Matchability score (M-score) to assess access to transplantation and posttransplant outcomes based on HLA match probability.

Methods: M-scores were calculated by comparing all recipients and donors with complete HLA-A, HLA-B, and HLA-DR data from the Australia and New Zealand Dialysis and Transplant Registry (July 1, 2006-December 31, 2023). Multivariable Cox regression was used to analyze associations between M-score quartiles and time to transplantation as well as transplantation outcomes.

Results: HLA data from 14 836 recipients and 7708 donors were used to generate M-scores. Of these, 10 760 recipients had available waitlist data and were included in the models. M-scores were normally distributed with a mean ± SD of 11.4 ± 0.9. The proportion of non-European Australians increased significantly with each quartile (ie, more difficult to HLA match), Q1: 16%, Q2: 26%, Q3: 40% Q4: 60% (P < 0.001). Compared with Q1, patients in Q4 were significantly less likely to receive a deceased donor kidney transplant (adjusted hazard ratio [aHR] 0.56; 95% confidence interval [CI], 0.52-0.60; P < 0.001) had the highest risk of death-censored graft loss (aHR 1.39; 95% CI, 1.01-1.91; P = 0.05) and acute rejection (aHR, 1.29; 95% CI, 1.09-1.52; P = 0.002).

Conclusions: The M-score identifies transplant recipients with difficult-to-match HLA profiles. Higher M-scores were associated with a lower likelihood of transplantation and an increased risk of death-censored graft loss and acute rejection. These findings highlight significant inequities in the current HLA-based algorithm for deceased donor allocation.

One of the major hurdles in solid organ transplantation is graft rejection, which must be prevented with lifelong general immunosuppression. However, modern maintenance immunosuppression is accompanied by serious side effects, such as an increased risk of infection and malignancies. The search for alternative therapies specifically controlling allogeneic responses is fueling renewed interest in extracorporeal photopheresis (ECP). Despite guideline indications for ECP in cardiothoracic transplantation, potential applications in liver and kidney transplantation have not been adequately investigated. Presently, limited understanding of the pharmacodynamic effects of ECP and lack of consensus biomarkers are hindering the development of standardized multiparametric assays to assess patient responses. This review explores current knowledge about immune responses after ECP in transplant recipients and collates a set of biomarkers associated with favorable treatment responses.

Extracorporeal photopheresis (ECP) is a safe and effective therapy with long-established indications in treating T cell-mediated immune diseases, including steroid refractory graft-versus-host disease and chronic rejection after heart or lung transplantation. The ECP procedure involves collecting autologous peripheral blood leucocytes that are driven into apoptosis before being reinfused intravenously. ECP acts primarily through in situ exposure of recipient dendritic cells and macrophages to apoptotic cells, which then suppress inflammation, promote specific regulatory T-cell responses, and retard fibrosis. Here, we explore the idea that macrophages exposed to apoptotic cell components from photopheresates acquire a tissue-reparative capacity that could be exploited therapeutically. Specifically, we consider innovative applications of ECP in resolving tissue injury after liver transplantation.

Extracorporeal photopheresis (ECP) is a therapeutic procedure that is increasingly recognized for its efficacy in treating immune-mediated diseases, including transplant rejection. Its main mechanism is ex vivo apoptosis induction in leukocytes from patients by incubation with 8-methoxypsoralen and irradiation with ultraviolet A light. The process involves DNA cross-linking, which leads to a cascade of events within the cell and ultimately to apoptosis induction. Although ECP has been used for almost 40 y, there remain many questions about its immunological mechanisms and therapeutic potential. Here, we review current knowledge about mechanisms of apoptosis induction in subsets of peripheral blood mononuclear cells and interactions of apoptotic leukocytes with immune cells. We also highlight the challenges of reproducibly inducing cell death in a clinical manufacturing procedure and propose innovative ways to improve and quality-control ECP photopheresates.

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy currently used as an add-on treatment for the prevention and management of organ rejection in lung transplantation. Thanks to its immunomodulatory properties and its ability to reduce the need for immunosuppressive therapies, ECP presents a promising therapeutic option, especially for high-risk patients with comorbidities, infections, or malignancies. This review provides a comprehensive overview of the current indications, clinical experience, and ongoing research surrounding the use of ECP in lung transplantation. Additionally, it delves into the current understanding of the mechanism of action of ECP, its potential role in lung transplantation, and the limitations identified in existing studies. By highlighting these aspects, the review aims to lay the groundwork for future research, which could further elucidate the mechanisms underlying this promising therapy and contribute to the standardization of therapeutic protocols.

Extracorporeal photopheresis (ECP) is emerging as an apoptotic cell-based therapy that suppresses alloimmunity, promotes donor-specific regulation, and reduces the need for conventional maintenance immunosuppression. ECP therapy is associated with regulatory T-cell proliferation, anti-inflammatory effects, and reduction of anti-HLA antibodies, making ECP a possible alternative or adjunct treatment for preventing and treating transplant rejection. Presently, we have a limited understanding of the mechanisms of ECP action, and clinical evidence for efficacy in kidney transplantation is sparse. Promising results in acute cellular or antibody-mediated rejection were reported, but beneficial effects in chronic settings are less evident. The absence of reliable markers for patient stratification and therapeutic monitoring further complicates its application. Working with the European Union-funded exTra network, our group is studying the therapeutic action of ECP in kidney transplantation with the ultimate goal of conducting a large multicenter study to standardize and harmonize treatment indications and approaches.