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After transplantation, Th1-mediated immune rejection is the predominant cause of graft failure. Th1 cell sensitization occurs through complex and context-dependent interaction among antigen-presenting cell subsets, particularly CD11b+ DCs (DC2) and CD103+ DCs (DC1). This interaction necessitates further investigation in the context of transplant immunity. We used well-established preclinical models of corneal transplantation and identified distinct roles of migratory CD103+ DC1 in influencing the outcomes of the grafted tissue. In recipients with uninflamed corneal beds, migratory CD103+ DC1 demonstrate a tolerogenic phenotype that modulates the immunogenic capacity of CD11b+ DC2 primarily mediated by IL-10, suppressing alloreactive CD4+ Th1 cells via the PD-L1/PD-1 pathway and enhancing Treg-mediated tolerance via αvβ8 integrin-activated TGF-β1, thus facilitating graft survival. Conversely, in recipients with inflamed and vascularized corneal beds, IFN-γ produced by CD4+ Th1 cells induced migratory CD103+ DC1 to adopt an immunostimulatory phenotype, characterized by the downregulation of regulatory markers, including αvβ8 integrin and IL-10, and the upregulation of IL-12 and costimulatory molecules CD80/86, resulting in graft failure. The adoptive transfer of ex vivo induced tolerogenic CD103+ DC1 (iDC1) effectively inhibited Th1 polarization and preserved the tolerogenic phenotype of their physiological counterparts. Collectively, our findings underscore the essential role played by CD103+ DC1 in modulating host alloimmune responses.

Rejection seriously affects the success of kidney transplantations. However, the molecular mechanisms underlying this rejection remain unclear. The GSE21374 and GSE36059 datasets were downloaded from the Gene Expression Omnibus (GEO) database. Next, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to infer the proportions of 22 immune cells. Moreover, infiltrating immune cell-related genes were identified using weighted gene co-expression network analysis (WGCNA), and enrichment analysis was conducted to observe their biological functions. Extreme Gradient Boosting (XGBoost) and Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression algorithms were used to screen hub genes. Quantitative real-time PCR was conducted to verify the number of immune cells and hub gene expression levels. The rejection and non-rejection groups showed significantly different distributions (P < 0.05) of eight immune cells (B cell memory, Plasma cells, mast cells, follicular helper T cells, T CD8 cells, Macrophages M1, T Cells CD4 memory activated, and gamma delta T cells). Subsequently, CD8A, CRTAM, GBP2, WARS, and VAMP5 were screened as hub genes using the XGBoost and LASSO algorithms and could be used as diagnostic biomarkers. Finally, differential analysis and quantitative real-time PCR suggested that CD8A, CRTAM, GBP2, WARS, and VAMP5 were upregulated in rejection samples compared to non-rejection samples. The present study identified five key infiltrating immune cell-related genes (CD8A, CRTAM, GBP2,WARS, and VAMP5) involved in kidney transplant rejection, which may explain the molecular mechanism of rejection in kidney transplantation development., (© 2024. The Author(s).)

It is essential to elucidate the molecular mechanisms underlying liver transplant tolerance and rejection. In cases of mouse liver transplantation between inbred strains, immunological rejection of the allograft is reduced with spontaneous apoptosis without immunosuppressive drugs, which differs from the actual clinical result. This may be because inbred strains are genetically homogeneous and less heterogeneous than others. We exploited outbred CD1 mice, which show highly heterogeneous genotypes among individuals, to search for biomarkers related to immune responses and to construct a model for predicting the outcome of liver allografting. Of the 36 mice examined, 18 died within 3 weeks after transplantation, while the others survived for more than 6 weeks. Whole-exome sequencing of the 36 donors revealed more than 9 million variants relative to the C57BL/6 J reference. We selected 6517 single-nucleotide and indel variants and performed machine learning to determine whether or not we could predict the prognosis of each genotype. Models were built by both deep learning with a one-dimensional convolutional neural network and linear classification and evaluated by leave-one-out cross-validation. Given that one short-lived mouse died early in an accident, the models perfectly predicted the outcome of all individuals, suggesting the importance of genotype collection. In addition, linear classification models provided a list of loci potentially responsible for these responses. The present methods as well as results is likely to be applicable to liver transplantation in humans., (© 2024. The Author(s).)

Background: Kidney transplantation from donors with human immunodeficiency virus (HIV) to recipients with HIV is an emerging practice. It has been performed since 2016 under the U.S. congressional HIV Organ Policy Equity Act and is currently approved for research only. The Department of Health and Human Services is considering expanding the procedure to clinical practice, but data are limited to small case series that did not include donors without HIV as controls., Methods: In an observational study conducted at 26 U.S. centers, we compared transplantation of kidneys from deceased donors with HIV and donors without HIV to recipients with HIV. The primary outcome was a safety event (a composite of death from any cause, graft loss, serious adverse event, HIV breakthrough infection, persistent failure of HIV treatment, or opportunistic infection), assessed for noninferiority (margin for the upper bound of the 95% confidence interval, 3.00). Secondary outcomes included overall survival, survival without graft loss, rejection, infection, cancer, and HIV superinfection., Results: We enrolled 408 transplantation candidates, of whom 198 received a kidney from a deceased donor; 99 received a kidney from a donor with HIV and 99 from a donor without HIV. The adjusted hazard ratio for the composite primary outcome was 1.00 (95% confidence interval [CI], 0.73 to 1.38), which showed noninferiority. The following secondary outcomes were similar whether the donor had HIV or not: overall survival at 1 year (94% vs. 95%) and 3 years (85% vs. 87%), survival without graft loss at 1 year (93% vs. 90%) and 3 years (84% vs. 81%), and rejection at 1 year (13% vs. 21%) and 3 years (21% vs. 24%). The incidence of serious adverse events, infections, surgical or vascular complications, and cancer was similar in the groups. The incidence of HIV breakthrough infection was higher among recipients of kidneys from donors with HIV (incidence rate ratio, 3.14; 95%, CI, 1.02 to 9.63), with one potential HIV superinfection among the 58 recipients in this group with sequence data and no persistent failures of HIV treatment., Conclusions: In this observational study of kidney transplantation in persons with HIV, transplantation from donors with HIV appeared to be noninferior to that from donors without HIV. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03500315.)., (Copyright © 2024 Massachusetts Medical Society.)

Liver transplantation is the definitive treatment for end-stage liver disease, yet T-cell mediated rejection (TCMR) remains a major challenge. This study aims to identify key genes associated with TCMR and their potential biological processes and mechanisms. The GSE145780 dataset was subjected to differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms to pinpoint key genes associated with TCMR. Gene Set Enrichment Analysis (GSEA), immune infiltration analysis, and regulatory networks were constructed to ascertain the biological relevance of these genes. Expression validation was performed using single-cell RNA-seq (scRNA-seq) data and liver biopsy tissues from patients. We identified 5 key genes (ITGB2, FCER1G, IL-18, GBP1, and CD53) that are associated with immunological functions, such as chemotactic activity, antigen processing, and T cell differentiation. GSEA highlighted enrichment in chemokine signaling and antigen presentation pathways. A lncRNA-miRNA-mRNA network was delineated, and drug target prediction yielded 26 potential drugs. Evaluation of expression levels in non-rejection (NR) and TCMR groups exhibited significant disparities in T cells and myeloid cells. Tissue analyses from patients corroborated the upregulation of GBP1, IL-18, CD53, and FCER1G in TCMR cases. Through comprehensive analysis, this research has identified 4 genes intimately connected with TCMR following liver transplantation, shedding light on the underlying immune activation pathways and suggesting putative targets for therapeutic intervention., (© 2024. The Author(s).)

This study develops an observational model to assess kidney function recovery and xenogeneic immune responses in kidney xenotransplants, focusing on gene editing and immunosuppression. Two brain-dead patients undergo single kidney xenotransplantation, with kidneys donated by minipigs genetically modified to include triple-gene knockouts (GGTA1, β4GalNT2, CMAH) and human gene transfers (hCD55 or hCD55/hTBM). Renal xenograft functions are fully restored; however, immunosuppression without CD40-CD154 pathway blockade is ineffective in preventing acute rejection by day 12. This rejection manifests as both T cell-mediated rejection and antibody-mediated rejection (AMR), confirmed by natural killer (NK) cell and macrophage infiltration in sequential xenograft biopsies. Despite donor pigs being pathogen free before transplantation, xenografts and recipient organs test positive for porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) by the end of the observation period, indicating reactivation and contributing to significant immunopathological changes. This study underscores the critical need for extended clinical observation and comprehensive evaluation using deceased human models to advance xenograft success., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Chronic antibody-mediated rejection in kidney transplantation is a common cause of graft loss in the late post-transplant period. In this process, the role of the classical complement activation pathway is crucial due to the formation of immune complexes between donor-specific antibodies (DSAs) and donor antigens and the attachment of the C1q complement fragment. This study aimed to determine the levels of circulating C1q immunocomplexes (CIC-C1q) and complement activation (CH50), in sensitized kidney transplant recipients (KTRs). In this cross-sectional study we used serum samples from KTRs with de novo or preformed DSAs ( n = 14), KTRs without DSAs ( n = 28), and 22 subjects with no history of chronic kidney disease (controls). C1q immunocomplexes and CH50 concentration in serum were measured with the enzyme immunoassay (EIA) kit MicroVue CIC-C1q (Quidel, Athens, OH, USA) and EIA kit MicroVue CH50 (Quidel, OH, USA), respectively. Higher concentrations of CIC-C1q was observed in KTRs with DSAs in comparison with controls and with KTRs with no DSAs (6.8 ± 2.7 and 4.8 ± 1.9 vs. 5.0 ± 1.2 μg Eq/mL, respectively, p < 0.01). We found no difference in CIC-C1q between KTRs with no DSAs and controls. CIC-C1q levels were positively correlated with DSA titer. CH50 levels were decreased in KTRs with DSAs in comparison with controls and KTRs with no DSAs (39 ± 15 vs. 68 ± 40 and 71 ± 34 U Eq/mL, respectively, p < 0.01). There was no difference in CH50 between DSA-negative KTRs and controls. Kidney transplant recipients with DSAs had increased serum levels of C1q immunocomplexes and increased classical pathway complement activation.

Introduction: The impact of deceased donor characteristics on kidney transplant outcomes is controversial. Correspondingly, the predictive performance of deceased donor scores remains moderate, and many transplant centers lack validated criteria for graft acceptance decisions. To better dissect donor-related risk from recipient and periprocedural variables, we analyzed outcomes of kidney donor pairs transplanted in different individuals., Methods: This study explored (a)symmetry of early outcomes of 328 cadaveric kidney transplant recipients from 164 donor pairs transplanted at three Eurotransplant centers. The primary discriminatory factor was (a)symmetry of partner graft function, defined as early graft loss or impaired graft function [estimated glomerular filtration rate (eGFR) <30 mL/min] 3 months after transplantation. We reasoned that a relevant impact of donor factors would result in a high concordance rate of limited graft function or failure., Results: The observed number of symmetric graft failure after transplantation was less than statistically expected (3 months: 1 versus 2, p = 0.89; and 12 months: 3 versus 5, p = 0.26). However, we found a trend toward an impaired 5-year graft survival of grafts with good function 3 months after transplantation but a failed or impaired partner graft compared to symmetrically well-functioning grafts (p = 0.09). Subsequently, we explored the impact of individual donor and recipient variables on early transplant outcomes. Generalized estimating equations after feature selection with LassoGEE bootstrap selected donor age, donor body mass index, and donor eGFR as the relevant risk factors., Discussion: Our findings indicate that donor factors impact early outcomes in kidney transplantation but may have a limited role in long-term graft survival, once a graft has been accepted for transplantation. Utilizing donor-based clinical scores has the potential to aid clinicians in acceptance decisions, giving them an estimate of individual posttransplant outcomes. However, the ultimate decision for acceptance should rest with clinicians, who must consider the complex interplay of donor factors, as well as recipient and periprocedural characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mahler, Friedl, Nusshag, Speer, Benning, Göth, Schaier, Sommerer, Mieth, Mehrabi, Renders, Heemann, Krautter, Schwenger, Echterdiek, Zeier, Morath and Kälble.)

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.

Identification of early signatures of immune rejection represents a key challenge in the clinical management of kidney transplant. To address such an issue, we enrolled 53 kidney transplant recipients without signs of graft rejection, no infectious episodes and no change in the immunosuppressive regimen in the last 6 months. An extensive immune profile revealed increased activation of the T cells, a decreased amount and growth ability of the Treg and a higher level of the T R3-56 regulatory T cell subset, described by us as involved in the preferential control of cytotoxic T lymphocytes. In renal transplant recipients, the high level of the T R3-56 cells associates with a reduction in both the amount and the growth ability of the Treg. Moreover, when the transplanted subjects were categorised according to their stable or unstable disease status, as defined by changes in serum creatinine ≥0.2 mg/dL in two consecutive detections, a higher T R3-56 level and defective Treg growth ability were observed to characterise patients with unstable graft control. Further studies are required to substantiate the hypothesis that immune profiling, including T R3-56 evaluation, might represent a valuable diagnostic tool to identify patients at risk of developing significant anti-donor allo-immune responses.

Competing Interests: Declaration of interests L.A. and M.S.-H. have a patent filed on immunosuppressant-resistant T cells for adoptive immunotherapy (EP2021/072651).

Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1A KO 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1A KO 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells., Competing Interests: Declaration of interests C.R.M., A.C.M., P.B.B., A.J.C., F.M.M., M.L.W., J.J.R., L.J.C., C.K., F.L., and B.Y. were employees of Beam Therapeutics when the work was conducted and are shareholders in the company. Beam Therapeutics has filed patent applications based on this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cytomegalovirus (CMV) infection is related to acute rejection and graft loss after kidney transplantation, though the underlying mechanism remains largely unknown. Some CMV strains produce a peptide that is identical to a peptide sequence found in the leader peptide of specific HLA-A and -C alleles. In this retrospective study of 351 kidney transplantations, we explored whether CMV-seropositive recipients without the VMAPRTLIL, VMAPRTLLL or VMAPRTLVL HLA class I leader peptide receiving a transplant from a donor with this peptide, faced an increased risk of T-cell-mediated rejection (TCMR) in the first 90 days after transplantation. An independent case-control cohort was used for validation (n = 122). The combination of recipient CMV seropositivity with the VMAPRTLIL peptide mismatch was associated with TCMR with a hazard ratio (HR) of 3.06 (p = 0.001) in a multivariable analysis. Similarly, the VMAPRTLLL peptide mismatch was associated with TCMR revealing a HR of 2.61 (p = 0.008). Transplantations featuring either a VMAPRTLIL or a VMAPRTLLL peptide mismatch had a significantly higher cumulative TCMR incidence (p < 0.0001), with the primary impact observed in the first 2 weeks post-transplantation. The findings could be validated in an independent cohort. Together, our data strongly suggest that CMV-positive recipients without an HLA peptide identical to a CMV peptide yet transplanted with a donor who does possess this peptide, have a significantly increased risk of early TCMR. Considering the prevention of such an leader peptide mismatch in these patients or adjusting immunosuppression protocols accordingly may hold promise in reducing the incidence of early TCMR., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Backgrounds: Acute transplant rejection is a major component of poor prognoses for organ transplantation. Owing to the multiple complex mechanisms involved, new treatments are still under exploration. Endometrial regenerative cells (ERCs) have been widely used in various refractory immune-related diseases, but the role of ERC-derived exosomes (ERC-Exos) in alleviating transplant rejection has not been extensively studied. Signaling lymphocyte activation molecule family 6 (SLAMF6) plays an important role in regulating immune responses. In this study, we explored the main mechanism by which ERC-Exos loaded with siSLAMF6 can alleviate allogeneic transplant rejection., Methods: C57BL/6 mouse recipients of BALB/c mouse kidney transplants were randomly divided into four groups and treated with exosomes. The graft pathology was evaluated by H&E staining. Splenic and transplanted heart immune cell populations were analyzed by flow cytometry. Recipient serum cytokine profiles were determined by enzyme-linked immunosorbent assay (ELISA). The proliferation and differentiation capacity of CD4 + T cell populations were evaluated in vitro. The α-2,6-sialylation levels in the CD4 + T cells were determined by SNA blotting., Results: In vivo, mice treated with ERC-siSLAMF6 Exo achieved significantly prolonged allograft survival. The serum cytokine profiles of the recipients were significantly altered in the ERC-siSLAMF6 Exo-treated recipients. In vitro, we found that ERC-siSLAMF6-Exo considerably downregulated α-2,6-sialyltransferase (ST6GAL1) expression in CD4 + T cells, and significantly reduced α-2,6-sialylation levels. Through desialylation, ERC-siSLAMF6 Exo therapy significantly decreased CD4 + T cell proliferation and inhibited CD4 + T cell differentiation into Th1 and Th17 cells while promoting regulatory T cell (Treg) differentiation., Conclusions: Our study indicated that ERC-Exos loaded with siSLAMF6 reduce the amount of sialic acid connected to α-2,6 at the end of the N-glycan chain on the CD4 + T cell surface, increase the number of therapeutic exosomes endocytosed into CD4 + T cells, and inhibit the activation of T cell receptor signaling pathways, which prolongs allograft survival. This study confirms the feasibility of using ERC-Exos as natural carriers combined with gene therapy, which could be used as a potential therapeutic strategy to alleviate allograft rejection., (© 2024. The Author(s).)

Competing Interests: The authors declare no funding or conflicts of interest.

Therapeutic plasma exchange (TPE) is a cornerstone treatment for antibody-mediated rejection (AMR) post-organ transplantation, aiming to eliminate pathogenic donor-specific HLA antibodies (DSA). However, limitations in HLA antibody interpretation due to the prozone-like effect (PLE) can lead to inaccurate assessment of treatment efficacy. We present a case of a heart transplant recipient with suspected AMR, where an unexpected increase in DSA levels post-TPE prompted investigation into PLE. Solid-phase Luminex assays were employed to detect HLA antibodies. Serum was run neat as well as after treatment with ethylenediaminetetraacetic acid (EDTA). Nephelometry was used to detect complement levels. Laboratory analysis of pre-TPE serum revealed higher DSA levels with EDTA treatment, characteristic of PLE. Complement measurements supported complement-mediated interference in the pre-TPE sample. This case underscores the importance of being aware that PLE can occur in HLA testing and can impact the interpretation of TPE efficacy for AMR., (© 2024 Wiley Periodicals LLC.)

Background: Cartilage is a crucial tissue in vascularized composite allotransplantation (VCA) and plays a pivotal role in restoring motor function, especially in joint allotransplantation. Nevertheless, our understanding of immune rejection in cartilage remains limited and contentious. This study seeks to investigate the immune rejection of cartilage in a large animal model of VCA., Methods: Cartilage, including articular cartilage and meniscus, as well as skin, muscle and lymph node, was retrieved from a swine heterotopic VCA graft when the skin of the graft suffered from grade III-IV rejection. Histologic examination, transmission electron microscopy and immunofluorescent staining were used to investigate immune rejection., Results: Histologic examination revealed the infiltration of inflammatory cells and tissue destruction in cartilage. Transmission electron microscopy confirmed tissue damage and necrosis in cartilage. However, cartilage exhibited milder tissue damage when compared to rejected skin and muscle. Immunofluorescent staining revealed the activation of both the innate and adaptive immune systems, accompanied by an up-regulation of cell death biomarkers, including apoptosis and pyroptosis, in the rejected cartilage., Conclusion: Our study demonstrates that cartilage is not immunologically privileged and undergoes immune rejection concurrently with skin and muscle in the VCA graft, though with less severe inflammation and rejection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: The scarcity of suitable donor organs has led to the inclusion of Expanded Criteria Donor (ECD) kidneys to augment the donor pool, despite potential concerns regarding post-transplant outcomes., Methods: This retrospective study analyzed the clinical outcomes of a cohort of 317 kidney transplant recipients from deceased donors at a single center between 2008 and 2018. Patients were categorized into ECD and Standard Criteria Donor (SCD) groups, with primary nonfunctioning grafts excluded. Comprehensive laboratory evaluations were conducted, including HLA typing and serum creatinine levels. Immunosuppressive regimens were standardized, and statistical analyses were performed using the SPSS program., Results: The sample consisted of 83 (26.18%) patients who received kidney transplants from ECDs and 234 (73.82%) from SCDs. The ECD group showed a longer cold ischemia time (p = 0.019) and a higher rate of delayed graft function (DGF) compared with the SCD group. No significant differences were observed in graft survival (p = 0.370) or patient survival (p = 0.993) between the ECD and SCD groups. However, differences in graft survival were noted between the groups when stratified by DGF status: ECD with DGF vs. ECD without DGF (p = 0.029), ECD with DGF vs. SCD with DGF (p = 0.188), ECD with DGF vs. SCD without DGF (p = 0.022), ECD without DGF vs. SCD with DGF (p = 0.014), ECD without DGF vs. SCD without DGF (p = 0.340), and SCD with DGF vs. SCD without DGF (p = 0.195). No differences in patient survival rates were observed among these groups for all pairwise comparisons (p > 0.05) when stratified by donor criteria and DGF status., Conclusions: Graft and patient survival rates were comparable between ECD and SCD kidney transplant recipients., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: The effect of belatacept on BK polyomavirus (BKPyV) control remains largely unknown., Methods: This is a propensity matched retrospective cohort study in adult kidney transplant recipients (KTR) transplanted between 2016-2020 who received a belatacept- versus tacrolimus-based immunosuppression regimen. A continuous time multi-state Markov model was used to evaluate BKPyV replication dynamics (BKPyV-dyn). Three BKPyV-dyn states were defined: BKPyV-dyn1 (viral load <3 log 10 ), BKPyV-dyn2 (viral load ≥ 3 log 10 and ≤4 log 10 ), and BKPyV-dyn3 (viral load >4 log 10 )., Results: Two hundred eighty KTR on belatacept- and 280 KTR on tacrolimus-based regimens were compared. The probability of transitioning between BKPyV-dyn states and time spent in each state in both groups was comparable. Total duration in BKPyV-dyn-1 was 632.1 days (95% CI 612.1, 648.5) for belatacept versus 615.2 days (95% CI 592.5, 635.8) for tacrolimus, BKPyV-dyn-2 was 49.2 days (95% CI 41.3, 58.4) for belatacept versus 55.6 days (95% CI 46.5, 66.8) for tacrolimus, and BKPyV-dyn-3 was 48.7 days (95% CI 37.1, 363.1) for belatacept versus 59.2 days (95% CI 45.8, 73.5) for tacrolimus. BKPyV associated nephropathy (PyVAN) occurred in 3.9% in belatacept- and 3.9% tacrolimus-treated KRT (P > .9)., Conclusions: Compared with tacrolimus-based immunosuppression, belatacept based immunosuppression was not associated with increased risk of BKPyV-DNAemia or nephropathy., (© 2024 Wiley Periodicals LLC.)

Pathophysiologic function of B cells in graft rejection has been well recognized in transplantation. B cells promote alloantigen-specific T-cell response and secrete antibodies that can cause antibody-mediated graft failures and rejections. Therefore, strategies targeting B cells, for example, B-cell depletion, have been used for the prevention of both acute and chronic rejections. Interestingly, however, recent mounting evidence indicates that subsets of B cells yet to be further identified can display potent immune regulatory functions, and they contribute to transplantation tolerance and operational tolerance in both experimental and clinical settings, respectively. In this review, we integrate currently available information on B-cell subsets, including T-cell Ig domain and mucin domain 1-positive transitional and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive memory B cells, displaying immune regulatory functions, with a focus on transplantation tolerance, by analyzing their mechanisms of action. In addition, we will discuss potential T-cell Ig domain and mucin domain 1-positive and T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domain-positive B cell-based strategies for the enhancement of operational tolerance in transplantation patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The lifelong administration of immunosuppressants remains the largest drawback in vascularized composite allotransplantation (VCA). Therefore, developing alternative strategies to minimize the long-term use of immunosuppressive agents is crucial. This study investigated whether full-spectrum bright light therapy (FBLT) combined with short-term immunosuppressant therapy could prolong VCA survival in a rodent hindlimb model., Methods: Hindlimb allotransplantation was conducted from Brown-Norway to Lewis rats, and the rats were divided into 4 groups. Group 1 did not receive treatment as a rejection control. Group 2 received FBLT alone. Group 3 was treated with short-term antilymphocyte serum (ALS) and cyclosporine A (CsA). Group 4 was administered short-term ALS/CsA combined with FBLT for 8 weeks. Peripheral blood and transplanted tissues were collected for analysis., Results: The results revealed median survival time of FBLT alone (group 2) did not increase allograft survival compared with the control (group 1). However, in group 4, FBLT combined with short-term ALS/CsA, median composite tissue allograft survival time (266 days) was significantly prolonged compared with groups 1 (11 days), 2 (10 days), and 3 (41 days) ( P < 0.01). Group 4 also showed a significant increase in regulatory T cells ( P = 0.04) and transforming growth factor-β1 levels ( P = 0.02), and a trend toward a decrease in interleukin-1β levels ( P = 0.03) at 16 weeks after transplantation as compared with control (group 1)., Conclusions: FBLT combined with short-term immunosuppressants prolonged allotransplant survival by modulating T-cell regulatory functions and antiinflammatory cytokine expression. This approach could be a potential strategy to increase VCA survival., Clinical Relevance Statement: Full-spectrum light therapy could be a potential strategy to increase vascularized composite allotransplant survival., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Normothermic ex vivo liver perfusion (NEVLP) is an exciting strategy to preserve livers prior to transplant, however, the effects of NEVLP on the phenotype of tissue-resident immune cells is largely unknown. The presence of tissue-resident memory T cells (TRM) in the liver may protect against acute rejection and decrease allograft dysfunction. Therefore, we investigated the effects of NEVLP on liver TRMs and assessed the ability of anti-inflammatory cytokines to reduce TRM activation during NEVLP., Methods: Rat livers underwent NEVLP with or without the addition of IL-10 and TGF-β. Naïve and cold storage livers served as controls. Following preservation, TRM T cell gene expression profiles were assessed through single cell RNA sequencing (scRNA-seq). Differential gene expression analysis was performed with Wilcoxon rank sum test to identify differentially expressed genes (DEGs) associated with a specific treatment group. Using the online Database for Annotation, Visualization and Integrated Discovery (DAVID), gene set enrichment was then conducted with Fisher's exact test on DEGs to highlight differentially regulated pathways and functional terms associated with treatment groups., Results: Through scRNA-seq analysis, an atlas of liver-resident memory T cell subsets was created for all livers. TRM T cells could be identified in all livers, and through scRNA-seq, DEG was identified with Wilcoxon rank sum test at FDR < 0.05. Based on the gene set enrichment analysis of DEGs using Fisher's exact test, NEVLP is associated with downregulation of multiple gene enrichment pathways associated with surface proteins. Furthermore, NEVLP with anti-inflammatory cytokines was associated with down regulation of 52 genes in TRM T cells when compared to NEVLP alone (FDR <0.05), most of which are pro-inflammatory., Conclusion: This is the first study to create an atlas of liver TRM T cells in the rat liver undergoing NEVLP and demonstrate the effects of NEVLP on liver TRM T cells at the single cell gene expression level., Competing Interests: Declaration of competing interest Nothing to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations., Methods: The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached., Results: A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk., Conclusion: The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy., (© 2024. The Author(s).)

Multi-organ transplantation involves the transplant of two or more organs from a single donor into a single recipient; in most cases, one of these organs is a kidney. Multi-organ transplantation is uncommon in pediatric transplantation but can be life-saving or significantly life-improving for children with rare diseases, including primary heart, liver, pancreas, or intestinal failure with secondary kidney failure, metabolic disorders, and genetic conditions causing multi-organ dysfunction. This manuscript reviews the current state of pediatric multi-organ transplantation that includes a kidney, with a focus on indications, evaluation, and key differences in management compared to kidney-alone transplantation. Guidelines and consensus statements for pediatric multi-organ transplantation are nonexistent; this review condenses reported statistics and peer-reviewed expert opinion while highlighting areas in need of further research., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: Delayed graft function (DGF) is a common condition that necessitates dialysis during the first week after transplantation. Although DGF rarely occurs following living-donor kidney transplantation (LDKT), it may eventually lead to acute or chronic graft rejection. This study aimed to assess the risk factors for DGF in patients who underwent LDKT., Methods: A systematic review and meta-analysis of studies published before August 2022 was conducted using the PubMed, Science Direct, Cochrane, and Directory of Open Access Journal (DOAJ) databases. The review included studies that assessed the incidence of DGF following LDKT, and examined its risk factors, while excluding studies involving deceased donors. Potential risk factors were analyzed using pooled mean differences or odds ratios with 95% confidence intervals (CIs). Review Manager 5.3 was used for the meta-analysis., Results: Among the 13 included studies, 3685 cases of DGF were identified in a total of 113,261 patients (3.25%). Potential risk factors for DGF following LDKT were examined across several aspects, including donor, recipient, donor/recipient relationship, and immunological and intraoperative factors. The identified risk factors included older donors (P = 0.07), male recipients (P < 0.0001), higher recipient body mass index (BMI) (P < 0.0001), non-white recipients (P < 0.0001), pre-existing diabetes (P < 0.0001), pre-existing hypertension (P = 0.01), history of dialysis (P < 0.0001), re-transplantation (P = 0.004), unrelated donor/recipient (P = 0.02), ABO incompatibility (P < 0.0001), higher panel reactive antibody (PRA) levels (P < 0.0001), utilization of right kidney (P < 0.0001), and longer cold ischemia time (CIT) (P = 0.004)., Conclusion: Several factors related to the donor, recipient, donor/recipient relationship, and immunological and intraoperative aspects were identified as potential risk factors for the development of DGF following LDKT. Addressing and optimizing these factors may improve the long-term outcomes of LDKT., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute allograft rejection is a well-known complication of liver transplantation (LT). The incidence, epidemiology, and outcomes of acute rejection have not been well described in Australia. We retrospectively studied consecutive adults who underwent deceased donor LT at a single center between 2010 and 2020. Donor and recipient data at the time of LT and recipient outcomes were collected from a prospective LT database. Liver biopsy reports were reviewed, and only a graft's first instance of biopsy-proven acute rejection was analyzed. During the study period, 796 liver transplants were performed in 770 patients. Biopsy-proven rejection occurred in 34.9% of transplants. There were no significant changes in the incidence of rejection over time (linear trend p =0.11). The median time to the first episode of rejection was 71 days after LT: 2.2% hyperacute, 50.4% early (≤90 d), and 47.5% late rejection (>90 d). Independent risk factors for rejection were younger recipient age at transplant (aHR 0.98 per year increase, 95% CI: 0.97-1.00, p =0.01), and ABO-incompatible grafts (aHR 2.55 vs. ABO-compatible, 95% CI: 1.27-5.09, p <0.01) while simultaneous multiorgan transplants were protective (aHR 0.21 vs. LT only, 95% CI: 0.08-0.58, p <0.01). Development of acute rejection (both early and late) was independently associated with significantly reduced graft (aHR 3.13, 95% CI: 2.21-4.42, p <0.001) and patient survival (aHR 3.42, 95% CI: 2.35-4.98, p <0.001). In this 11-year Australian study, acute LT rejection occurred in 35%, with independent risk factors of younger recipient age and ABO-incompatible transplant, while having a simultaneous multiorgan transplant was protective. Acute rejection was independently associated with reduced graft and patient survival after adjustment for other factors., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Organ transplantation remains the most optimal strategy for patients with end-stage organ failure. However, prevailing methods of immunosuppression are marred by adverse side effects, and allograft rejection remains common. It is imperative to identify and comprehensively characterize the cell types involved in allograft rejection, and develop therapies with greater specificity. There is increasing recognition that processes mediating allograft rejection are the result of interactions between innate and adaptive immune cells. Macrophages are heterogeneous innate immune cells with diverse functions that contribute to ischemia-reperfusion injury, acute rejection, and chronic rejection. Macrophages are inflammatory cells capable of innate allorecognition that strengthen their responses to secondary exposures over time via "trained immunity." However, macrophages also adopt immunoregulatory phenotypes and may promote allograft tolerance. In this review, we discuss the roles of macrophages in rejection and tolerance, and detail how macrophage plasticity and polarization influence transplantation outcomes. A comprehensive understanding of macrophages in transplant will guide future personalized approaches to therapies aimed at facilitating tolerance or mitigating the rejection process., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Sirtuins (SIRT) family plays a key role in the diagnosis and treatment of many renal diseases, but no studies have been reported in acute rejection of kidney transplantation. The aim of this study was to explore the diagnostic value of SIRT family change characteristics in acute rejection of kidney transplantation., Methods: We first explored the SIRT family expression profile in renal tissues using the HPA database; subsequently, we explored the potential biological functions and mechanistic changes during acute rejection of kidney transplantation by GSEA enrichment analysis. The Cibersort algorithm specifies the level of immune cell infiltration and explores the correlation between the SIRT family and immune cells using correlation analysis; Next, we constructed a diagnostic model using "Logistic regression analysis" and "Nomogram model", and evaluated the diagnostic model using calibration curves and ROC curves, and the decision curve (DCA) was used to evaluate the clinical diagnostic value of SIRT family changes; Finally, we constructed a model of acute rejection of rat kidney transplantation, and assessed rat kidney function by detecting the levels of urea nitrogen and creatinine in serum. Meanwhile, the expression level of SIRT family in kidney tissues was initially verified by transcriptome sequencing and RT-PCR., Results: We found that all seven SIRT family members were located and expressed in renal tissues. The results of enrichment analysis revealed that a large number of immune-related biological functions and pathways are activated during acute rejection of kidney transplantation, the difference was statistically significant (p < 0.05). The Cibersort algorithm revealed significant changes in the level of infiltration of 10 immune cells (p < 0.05), while correlation analysis revealed a strong link between the SIRT family and immune cells (p < 0.05). We constructed a diagnostic model for acute rejection using seven SIRT families, and the ROC curves(AUC = 0.71)and calibration curves proved their good diagnostic value, and the DCA curves also proved the role of SIRT families in clinical decision-making. Next, we again demonstrated the good diagnostic performance of the SIRT family in ABMR and TCMR, respectively(ROC curves:AUC = 0.64，AUC = 0.81). Finally, in a rat model of acute rejection of kidney transplantation, we found that renal function (BUN and creatinine) was significantly impaired in rats in the Allo group compared to rats in the Syn group (P < 0.05). Meanwhile, by transcriptome analysis and RT-PCR assay, we found that, except for SIRT1, the remaining SIRT family members were significantly changed in kidney tissues (P < 0.05)., Conclusion: The SIRT family has significant changes during acute rejection in kidney transplantation, and the SIRT family may be able to serve as a potential therapeutic target for alleviating acute rejection in kidney transplantation., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Allograft rejection, accompanied by a rise in proinflammatory cytokines, is a leading cause of morbidity and mortality after lung transplantation. Immunosuppressive treatments are routinely employed as an effective way to prevent rejection, however, there is still an unmet need to develop new strategies to reduce the damage caused to transplanted organs by innate inflammatory responses. Recent research has shown that activating the vagus nerve's efferent arm regulates cytokine production and improves survival in experimental conditions of cytokine excess, such as sepsis, hemorrhagic shock, ischemia-reperfusion injury, among others. The cholinergic anti-inflammatory pathway can provide a localized, fast, and discrete response to inflammation by controlling the neuroimmune response and preventing excessive inflammation. This review intends to assess and discuss, the influence of noninvasive vagal nerve stimulation for prophylactic measures and supporting treatment in patients undergoing organ transplantation rejection with a prominent T-cell mediated immune response as a means of attenuating inflammation and leukocyte infiltration of the graft vessels., Competing Interests: Declaration of competing interest I declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Immunological rejection is the most common reason for corneal transplantation failure. The importance of T cells in corneal allograft rejection is well demonstrated. Recent studies highlight that pigment epithelium-derived factor (PEDF) plays an immunoregulatory role in ocular diseases by enhancing the suppressive phenotype of regulatory T cells besides its other functions in neurotrophy and antiangiogenesis., Methods: The effects of PEDF on immune rejection were examined in rat models of corneal transplantation using slit-lamp microscope observation, immunohistochemistry, flow cytometry, and Western blot. In vitro, we demonstrated PEDF reduced alloreactive T-cell activation using real-time polymerase chain reaction, flow cytometry, and Western blot., Results: Topical administration of PEDF provided corneal transplantation rats with an improved graft survival rate of corneal allografts, reduced hemangiogenesis, and infiltration of immune cells in corneas, in particular, type 17 T helper cells while increased regulatory T cells. Moreover, nerve reinnervation within grafts was promoted in PEDF-treated recipient rats. In vitro, PEDF inhibited alloreactive T-cell activation via the c-Jun N-terminal kinase/c-Jun signaling pathway and upregulated the expressions of interleukin-10 and transforming growth factor-β, emphasizing the suppressive role of PEDF on immune responses., Conclusions: Our results underscore the feasibility of PEDF in alleviating corneal allograft rejection and further illustrate its potential in managing immune-related diseases., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Transplantation serves as the cornerstone of treatment for patients with end-stage organ disease. The prevalence of complications, such as allograft rejection, infection, and malignancies, underscores the need to dissect the complex interactions of the immune system at the single-cell level. In this review, we discuss studies using mass cytometry or cytometry by time-of-flight, a cutting-edge technology enabling the characterization of immune populations and cell-to-cell interactions in granular detail. We review the application of mass cytometry in human and experimental animal studies in the context of transplantation, uncovering invaluable contributions of the tool to understanding rejection and other transplant-related complications. We discuss recent innovations that have the potential to streamline and standardize mass cytometry workflows for application to multisite clinical trials. Additionally, we introduce imaging mass cytometry, a technique that couples the power of mass cytometry with spatial context, thereby mapping cellular interactions within tissue microenvironments. The synergistic integration of mass cytometry and imaging mass cytometry data with other omics data sets and high-dimensional data platforms to further define immune dynamics is discussed. In conclusion, mass cytometry technologies, when integrated with other tools and data, shed light on the intricate landscape of the immune response in transplantation. This approach holds significant potential for enhancing patient outcomes by advancing our understanding and facilitating the development of new diagnostics and therapeutics., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The effects of COVID-19 on the immune profile of kidney transplant recipients are unknown. Immunosuppression adjustment during the illness can increase the risk for de novo donor-specific anti-HLA antibodies (DSA) and acute rejection episodes. This single-center retrospective study includes adult kidney transplant recipients diagnosed with COVID-19 between March 2020 and December 2022, screened for anti-HLA antibodies (AbHLA) pre-transplant and after COVID-19. Analyzed data comprised demographics, immunosuppressive therapy before and during the illness, hospitalization rate, and AbHLA specificity. Two hundred sixty-seven transplant recipients were included and divided according to the pre-transplant AbHLA profile: absent [PRA- (n = 206, 77%)], non-DSA (N = 46, 17%), and DSA+ (n = 15, 6%). The DSA+ group was younger (40.5 ± 16.5; PRA- 50.3 ± 13.4; non-DSA 49.3 ± 11.7 years; p = 0.02). The hospitalization rate was higher in groups with preformed AbHLA (DSA+ n = 8, 53%; non-DSA = 24, 52%; PRA- n = 54, 26%; p < 0.01). Immunosuppression was maintained in 222 (83%), withdrawn in 33 (12%), and reduced in 11 (4%) cases without difference among groups. Twenty-two (8%) cases of de novo DSA were observed after COVID-19 [PRA-, n = 16 (73%) and non-DSA, n = 6 (27%)]. In the DSA+ group, the AbHLA profile remained stable. There were 6 (2%) cases of post-COVID-19 antibody-mediated rejection (DSA+ n = 4, 66%; non-DSA n = 1, 17%, PRA- n = 1, 17%) without T cell-mediated rejection cases. Post-COVID-19 de novo DSA was more frequent in groups without pre-transplant AbHLA, not having association with changes in immunosuppressive therapy., Competing Interests: Declaration of competing interest Authors have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunoglobulin glycosylation is a pivotal mechanism that drives the diversification of antibody functions. The composition of the IgG glycome is influenced by environmental factors, genetic traits and inflammatory contexts. Differential IgG glycosylation has been shown to intricately modulate IgG effector functions and has a role in the initiation and progression of various diseases. Analysis of IgG glycosylation is therefore a promising tool for predicting disease severity. Several autoimmune and alloimmune disorders, including critical and potentially life-threatening conditions such as systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and antibody-mediated kidney graft rejection, are driven by immunoglobulin. In certain IgG-driven kidney diseases, including primary membranous nephropathy, IgA nephropathy and lupus nephritis, particular glycome characteristics can enhance in situ complement activation and the recruitment of innate immune cells, resulting in more severe kidney damage. Hypofucosylation, hypogalactosylation and hyposialylation are the most common IgG glycosylation traits identified in these diseases. Modulating IgG glycosylation could therefore be a promising therapeutic strategy for regulating the immune mechanisms that underlie IgG-driven kidney diseases and potentially reduce the burden of immunosuppressive drugs in affected patients., (© 2024. Springer Nature Limited.)

Background: T cells drive acute cellular rejection (ACR) and its progression to chronic lung allograft dysfunction (CLAD) following lung transplantation. International Society for Heart and Lung Transplantation grade A1 ACR without associated allograft dysfunction is often untreated, yet some patients develop progressive graft dysfunction. T-cell composition of A1 ACR lesions may have prognostic value; therefore, protein-level and epigenetic techniques were applied to transbronchial biopsy tissue to determine whether differential T-cell infiltration in recipients experiencing a first episode of stable grade A1 ACR (StA1R) is associated with early CLAD., Methods: Sixty-two patients experiencing a first episode of StA1R were divided into those experiencing CLAD within 2 years (n = 13) and those remaining CLAD-free for 5 or more years (n = 49). Imaging mass cytometry (IMC) was used to profile the spectrum and distribution of intragraft T cell phenotypes on a subcohort (n = 16; 8 early-CLAD and 8 no early-CLAD). Immunofluorescence was used to quantify CD4 + , CD8 + , and FOXP3 + cells. Separately, CD3 + cells were fluorescently labeled, micro-dissected, and the degree of Treg-specific demethylated region methylation was determined., Results: PhenoGraph unsupervised clustering on IMC revealed 50 unique immune cell subpopulations. Methylation and immunofluorescence analyses demonstrated no significant differences in Tregs between early-CLAD and no early-CLAD groups. Immunofluorescence revealed that patients who developed CLAD within 2 years of lung transplantation showed greater CD8 + T cell infiltration compared to those who remained CLAD-free for 5 or more years., Conclusions: In asymptomatic patients with a first episode of A1 rejection, greater CD8 + T cell content may be indicative of worse long-term outlook., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Advancements in preclinical xenotransplant studies have opened doors for clinical heart and kidney xenotransplantation. This review assesses recent progress in lung xenotransplantation research and its potential clinical implications., Recent Findings: The efficacy of the humanized von Willebrand factor in reducing platelet sequestration in ex-vivo and in-vivo lung xenotransplant models was showcased. Combining human tissue factor pathway inhibitor and CD47 expression with selectin and integrin inhibition delayed neutrophil and platelet sequestration. Enhanced expression of human complement regulatory proteins and thrombomodulin in genetically engineered pig lungs improved graft survival by reducing platelet activation and modulating coagulation disruptions. Knocking out the CMAH gene decreased antibody-mediated inflammation and coagulation activation, enhancing compatibility for human transplantation. Furthermore, CMAH gene knockout in pigs attenuated sialoadhesin-dependent binding of human erythrocytes to porcine macrophages, mitigating erythrocyte sequestration and anemia. Meanwhile, in-vivo experiments demonstrated extended survival of xenografts for up to 31 days with multiple genetic modifications and comprehensive treatment strategies., Summary: Experiments have uncovered vital insights for successful xenotransplantation, driving further research into immunosuppressive therapy and genetically modified pigs. This will ultimately pave the way for clinical trials designed to improve outcomes for patients with end-stage lung disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oxidative stress is an unavoidable process in kidney transplantation and is closely related to the development of acute rejection after kidney transplantation. This study aimed to investigate the biomarkers associated with oxidative stress and their potential biological functions during acute rejection of kidney transplants., Methods: We identified Hub genes using five machine learning algorithms based on differentially expressed genes (DEGs) in the kidney transplant acute rejection dataset GSE50058 and oxidative stress-related genes (OS) obtained from the MSigDB database, and validated them with the datasets GSE1563 and GSE9493, as well as with animal experiments; Subsequently, we explored the potential biological functions of Hub genes using single-gene GSEA enrichment analysis; The Cibersort algorithm was used to explore the altered levels of infiltration of 22 immune cells during acute rejection of renal transplantation, and a correlation analysis between Hub genes and immune cells was performed; Finally, we also explored transcription factors (TFs), miRNAs, and potential drugs that regulate Hub genes., Results: We obtained a total of 57 genes, which we defined as oxidative stress-associated differential genes (DEOSGs), after intersecting DEGs during acute rejection of kidney transplants with OSs obtained from the MSigDB database; The results of enrichment analysis revealed that DEOSGs were mainly enriched in response to oxidative stress, response to reactive oxygen species, and regulation of oxidative stress and reactive oxygen species; Subsequently, we identified one Hub gene as APOD using five machine learning algorithms, which were validated by validation sets and animal experiments; The results of single-gene GSEA enrichment analysis revealed that APOD was closely associated with the regulation of immune signaling pathways during acute rejection of kidney transplants; The Cibersort algorithm found that the infiltration levels of a total of 10 immune cells were altered in acute rejection, while APOD was found to correlate with the expression of multiple immune cells; Finally, we also identified 154 TFs, 12 miRNAs, and 12 drugs or compounds associated with APOD regulation., Conclusion: In this study, APOD was identified as a biomarker associated with oxidative stress during acute rejection of kidney transplants using multiple machine learning algorithms, which provides a potential therapeutic target for mitigating oxidative stress injury and reducing the incidence of acute rejection in kidney transplantation., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: The clinical relevance of preformed donor specific antibodies in the setting of a negative crossmatch (DSA + XM-) remains controversial. In this study we investigate the outcomes of patients with a DSA + XM- living donor (LDi) who proceeded with an HLA-incompatible (HLAi) transplant compared with those who waited for an HLA-compatible deceased donor (DDc)., Materials and Methods: We investigated 359 patients on the transplant waiting list who had at least one potential HLAi living donor, from which 203 DSA + XM- pairs were identified and outcomes analysed., Results: Out of 203 patients, 96 (47.3%) received a LD transplant: 52/96 (54.2%) a LDi, and 44/96 (45.8%) an alternative compatible LD. In addition, 107 patients out of 203(52.7%) waited for a DDc, of which 47(43.9%) were subsequently transplanted. Our adjusted analysis showed that the LDi transplantation did not offer a superior patient survival over waiting for a DDc transplant. For those transplanted, there was no difference in patient (p = 0.065) or death censored allograft survival (p = 0.37) between DDc and LDi recipients. However, there was a higher incidence of acute allograft rejection (p = 0.043) and antibody-mediated rejection (p = 0.005) in the LDi group. Having a high pre-transplant calculated reaction frequency and preformed DSA to both class I and class II antigens were associated with inferior outcomes in the LDi transplants., Conclusions: Given the lack of difference in allograft survival between LDi and DDc transplants, in the absence of an alternative compatible living donor, proceeding with a LDi should be supported despite a higher rejection risk, providing individual risk assessment and shared decision making is undertaken., Competing Interests: Declaration of competing interest The authors have no disclosures to declare related to this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Renal transplantation is the preferred treatment option for patients with end-stage renal disease (ESRD) in a clinical setting. Antibody mediated rejection (AMR) is one of the leading causes of graft dysfunction. To address the current shortcomings in the early diagnosis and treatment of AMR in clinical practice, this article analyzes the distribution of different circulating T follicular helper (cTfh) cell subtypes and B cell subpopulations in peripheral blood and detects the cytokine levels of chemokine ligand 13 (CXCL13), interleukin-21 (IL-21), and interleukin-4 (IL-4) related to cTfh cells in peripheral blood of kidney transplant recipients. Moreover, we also explore the correlation between cTfh cells, peripheral blood memory B cells, and AMR, their value as early predictive indicators of AMR, and explore potential therapeutic targets for AMR patients. Our results indicate that the proportion of cTfh cells increased at the onset of AMR, which plays an important role in antigen-specific B-cell immune regulation. Activation of cTfh cells in AMR patients correlates with phenotypes of memory B cells and plasma blasts. cTfh cells and memory B cells have promising diagnostic efficacies and predictive values for AMR. The proportion of cTfh cells to CD4 + T cells and the proportion of memory B cells to CD19 + B cells are correlated with serum creatinine levels, indicating that cTfh cells and memory B cells may be involved in the progression of AMR. In addition, the CXCL13, IL-21, and IL-4, which were associated with cTfh cells, may be involved in the onset of AMR., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

As a consequence of increased lifespan and rising number of elderly individuals developing end-stage organ disease, the higher demand for organs along with a growing availability for organs from older donors pose new challenges for transplantation. During aging, dynamic adaptations in the functionality and structure of the biological systems occur. Consistently, immunosenescence (IS) accounts for polydysfunctions within the lymphocyte subsets, and the onset of a basal but persistent systemic inflammation characterized by elevated levels of pro-inflammatory mediators. There is an emerging consensus about a causative link between such hallmarks and increased susceptibility to morbidities and mortality, however the role of IS in solid organ transplantation (SOT) remains loosely addressed. Dissecting the immune-architecture of immunologically-privileged sites may prompt novel insights to extend allograft survival. A deeper comprehension of IS in SOT might unveil key standpoints for the clinical management of transplanted patients., Competing Interests: Declaration of competing interest The Authors have no conflict of interests to disclosure., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Regulatory B cells (Bregs) is an indispensable element in inducing immune tolerance after liver transplantation. As one of the microRNAs (miRNAs), miR-29a-3p also inhibits translation by degrading the target mRNA, and yet the relationship between Bregs and miR-29a-3p has not yet been fully explored. This study aimed to investigate the impact of miR-29a-3p on the regulation of differentiation and immunosuppressive functions of memory Bregs (mBregs) and ultimately provide potentially effective therapies in inducing immune tolerance after liver transplantation., Methods: Flow cytometry was employed to determine the levels of Bregs in peripheral blood mononuclear cells. TaqMan low-density array miRNA assays were used to identify the expression of different miRNAs, electroporation transfection was used to induce miR-29a-3p overexpression and knockdown, and dual luciferase reporter assay was used to verify the target gene of miR-29a-3p., Results: In patients experiencing acute rejection after liver transplantation, the proportions and immunosuppressive function of mBregs in the circulating blood were significantly impaired. miR-29a-3p was found to be a regulator of mBregs differentiation. Inhibition of miR-29a-3p, which targeted nuclear factor of activated T cells 5 (NFAT5), resulted in a conspicuous boost in the differentiation and immunosuppressive function of mBregs. The inhibition of miR-29a-3p in CD19 + B cells was capable of raising the expression levels of NFAT5, thereby promoting B cells to differentiate into mBregs. In addition, the observed enhancement of differentiation and immunosuppressive function of mBregs upon miR-29a-3p inhibition was abolished by the knockdown of NFAT5 in B cells., Conclusions: miR-29a-3p was found to be a crucial regulator for mBregs differentiation and immunosuppressive function. Silencing miR-29a-3p could be a potentially effective therapeutic strategy for inducing immune tolerance after liver transplantation., (Copyright © 2024 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Acute cellular rejection (ACR) in heart transplant (HTx) recipients may be accompanied by cardiac cell damage with subsequent exposure to cardiac autoantigens and the production of cardiac autoantibodies (aABs). This study aimed to evaluate a peptide array screening approach for cardiac aABs in HTx recipients during ACR (ACR-HTx)., Methods: In this retrospective single-center observational study, sera from 37 HTx recipients, as well as age and sex-matched healthy subjects were screened for a total of 130 cardiac aABs of partially overlapping peptide sequences directed against structural proteins using a peptide array approach., Results: In ACR-HTx, troponin I (TnI) serum levels were found to be elevated. Here, we could identify aABs against beta-2-adrenergic receptor (β-2AR: EAINCYANETCCDFFTNQAY) to be upregulated in ACR-HTx (intensities: 0.80 versus 1.31, P = 0.0413). Likewise, patients positive for β-2AR aABs showed higher TnI serum levels during ACR compared with aAB negative patients (10.0 versus 30.0 ng/L, P = 0.0375). Surprisingly, aABs against a sequence of troponin I (TnI: QKIFDLRGKFKRPTLRRV) were found to be downregulated in ACR-HTx (intensities: 3.49 versus 1.13, P = 0.0025). A comparison in healthy subjects showed the same TnI sequence to be upregulated in non-ACR-HTx (intensities: 2.19 versus 3.49, P = 0.0205), whereas the majority of aABs were suppressed in non-ACR-HTx., Conclusions: Our study served as a feasibility analysis for a peptide array screening approach in HTx recipients during ACR and identified 2 different regulated aABs in ACR-HTx. Hence, further multicenter studies are needed to evaluate the prognostic implications of aAB testing and diagnostic or therapeutic consequences., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

This comprehensive review delves into the intricate dynamics between the immune system and bacterial infections in organ transplant recipients. Its primary objective is to fill existing knowledge gaps while critically assessing the strengths and weaknesses of current research. The paper accentuates the delicate balance that must be struck between preventing graft rejection through immunosuppression and maintaining robust immunity against bacterial threats. In this context, personalized medicine emerges as a transformative concept, offering the potential to revolutionize clinical outcomes by tailoring immunosuppressive regimens and vaccination strategies to the unique profiles of transplant recipients. By emphasizing the pivotal role of continuous monitoring, the review underscores the necessity for vigilant surveillance of transplant recipients to detect bacterial infections and associated immune responses early, thereby reducing the risk of severe infections and ultimately improving patient outcomes. Furthermore, the study highlights the significance of the host microbiome in shaping immune responses, suggesting that interventions targeting the microbiome hold promise for enhancing bacterial immunity in transplant recipients, both in research and clinical practice. In terms of future research directions, the review advocates for large-scale, longitudinal studies encompassing diverse patient cohorts to provide more comprehensive insights into post-transplant immune responses. It also advocates integrating multi-omics approaches, including genomics, transcriptomics, proteomics, and microbiome data, to understand immune responses and their underlying mechanisms. In conclusion, this review significantly enriches our understanding of immune responses in transplant recipients. It paves the way for more effective and personalized approaches to managing infections in this complex setting., (Copyright © 2024. Published by Elsevier B.V.)

C4d is the end degradation product of activated complement component C4b that appears during the early steps of the classical and lectin complement pathways. Within the primary sequence of C4d, there is a reactive thioester group that binds covalently to nearby surfaces, thus labeling the locations of complement activation. This feature makes C4d a target for immunohistochemical staining aimed to aid the diagnosis of, among others, the antibody-mediated rejection of transplanted organs, membranous glomerulonephritis, bullous pemphigoid, or inflammatory myopathies. However, the credibility of C4d immunostaining is debatable, as a high background in surrounding tissues and body fluids and diffused patterns of deposits in target structures are experienced with some of the available anti-C4d antibodies. Herein, we present an improved version of a rabbit anti-C4d antibody, originally raised against the C-terminal linear neoepitope of this complement fragment. Minor cross-reactivity with C4b and native C4 proteins, measured by ELISAs, as well as relatively low concentrations necessary for obtaining a specific signal in immunohistochemical analyses of formalin-fixed paraffin-embedded material, makes the improved antibody superior to commercially available rabbit monoclonal anti-C4d antibody SP91 dedicated to ex vivo diagnostics, as demonstrated by the staining of a panel of kidney transplant biopsies.

Non-HLA antibodies against heterogeneous targets on endothelial cells have been associated with allograft injuries. The endothelial cell crossmatch (ECXM) is used in the detection of non-HLA antibodies but remains non-discriminatory for specific antibody identification. The primary objective of this study was to delineate the specific non-HLA antibody signatures associated with ECXM positivity and to determine the correlation of ECXM status and non-HLA antibody signatures on allograft health. Serum specimens from 25 lung transplant recipients (LTRs) and 13 renal transplant recipients (RTRs) were collected as part of clinical evaluation, and testing for angiotensin II receptor type 1 (AT1R) and donor-specific MHC class I chain-related gene A (MICA) antibodies and ECXM was performed. Remnant sera were tested for non-HLA antibodies using the LABScreen™ Autoantibody (LSAUT) Group 1, 2, and 3 kits (One Lambda, Inc., Los Angeles, CA, USA). In both cohorts, the concordance of AT1R and MICA together or individually with ECXM+ status was poor (<0.7), suggesting the presence of other unaccounted antibodies. Autoantibody profiling revealed three distinct clusters targeting fibrotic products, cytoskeletal proteins, and cell signaling molecules. A comparative analysis of ECXM+ and ECXM- specimens identified nine and five differentially expressed antibodies in the LTR and RTR cohorts, respectively. Employing machine learning techniques (variable importance, feature selection, ROC-AUC), we derived a five-antibody panel (TNFα, collagen V, CXCL11, GDNF, GAPDH) and a two-antibody panel (TNFα, CXCL9) that effectively discriminated between ECXM+ and ECXM- status in the LTR and RTR cohorts, respectively. Distinct antibody signatures were identified in LTR and RTR cohorts that correlated with ECXM+ status and were associated with allograft dysfunction.

Xenotransplantation of porcine hearts has become a promising alternative to human allotransplantation, where organ demand still greatly surpasses organ availability. Before entering the clinic, however, feasibility of cardiac xenotransplantation needs to be proven, ideally in the life supporting orthotopic pig-to-nonhuman primate xenotransplantation model. In this review, we shortly outline the last three decades of research and then discuss in detail its most recent advances. These include the genetic modifications of donor pigs to overcome hyperacute rejection and coagulation dysregulation, new organ preservation methods to prevent perioperative xenograft dysfunction, experimental immunosuppressive and immunomodulatory therapies to inhibit the adaptive immune system and systemic inflammation in the recipient, growth control concepts to avoid detrimental overgrowth of the porcine hearts in nonhuman primates, and lastly, the avoidance of porcine cytomegalovirus infections in donor pigs. With these strategies, consistent survival of 6-9 months was achieved in the orthotopic xenotransplantation model, thereby fulfilling the prerequisites for the initiation of a clinical trial., Competing Interests: ML and BR are founding members of XTransplant GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Längin, Bender, Schmoeckel and Reichart.)

Introduction: Kidney transplantation is the optimal treatment for end-stage kidney disease; however, premature allograft loss remains a serious issue. While many high-throughput omics studies have analyzed patient allograft biospecimens, integration of these datasets is challenging, which represents a considerable barrier to advancing our understanding of the mechanisms of allograft loss., Methods: To facilitate integration, we have created a curated database containing all open-access high-throughput datasets from human kidney transplant studies, termed NephroDIP (Nephrology Data Integration Portal). PubMed was searched for high-throughput transcriptomic, proteomic, single nucleotide variant, metabolomic, and epigenomic studies in kidney transplantation, which yielded 9,964 studies., Results: From these, 134 studies with available data detailing 260 comparisons and 83,262 molecules were included in NephroDIP v1.0. To illustrate the capabilities of NephroDIP, we have used the database to identify common gene, protein, and microRNA networks that are disrupted in patients with chronic antibody-mediated rejection, the most important cause of late allograft loss. We have also explored the role of an immunomodulatory protein galectin-1 (LGALS1), along with its interactors and transcriptional regulators, in kidney allograft injury. We highlight the pathways enriched among LGALS1 interactors and transcriptional regulators in kidney fibrosis and during immunosuppression., Discussion: NephroDIP is an open access data portal that facilitates data visualization and will help provide new insights into existing kidney transplant data through integration of distinct studies and modules (https://ophid.utoronto.ca/NephroDIP)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Boshart, Petrovic, Abovsky, Pastrello, Farkona, Manion, Neupane, Allen, Jurisica and Konvalinka.)