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Kidney transplantation is the optimal treatment for end-stage renal failure patients. However, its long-term survival rate remains relatively low, with immune rejection being a crucial risk factor. In recent years, notable progress has been made in the study of the immune regulation network in kidney transplantation. The key roles and molecular mechanisms of diverse immune cells in rejection have been gradually clarified. Innate immune components (such as neutrophils, macrophages, natural killer cells, etc.) activate inflammatory signals via pattern recognition receptors and collaborate with the complement system and platelets to mediate early graft damage. In adaptive immunity, T/B cell subsets drive donor-specific immune responses through direct/indirect recognition pathways, forming the core effector mechanism of immune rejection. We retrieved relevant articles from databases such as PubMed and Web of Science using keywords including \"kidney transplantation\" and \"immunity\", focusing on the most recent research published in the past decade. Articles were screened and evaluated based on high scientific standards regarding research quality and relevance. This review centers on the dynamic interaction network between innate and adaptive immunity after kidney transplantation. It systematically elaborates the roles of various immune cell subsets throughout the rejection process and further explores the application prospects of xenogeneic kidney transplantation, immune monitoring techniques, and precision individualized immunotherapy, all with the aim of exploring new directions for future kidney transplantation immunology research.

Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes.

Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood–brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed.

Deletion of p53 and pRB leads to gene instability and replication errors that contribute to oncogenesis. [...]given the very unfavourable prognosis of these tumours, it seems legitimate to perform surgery and completely stop immunosuppression. Conflict of 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.

Antibody-mediated rejection is currently the leading cause of transplant failure. Prevailing dogma predicts that B cells differentiate into anti-donor-specific antibody (DSA)producing plasma cells only with the help of CD4+ T cells. Yet, previous studies have shown that dependence on helper T cells decreases when high amounts of protein antigen are recruited to the spleen, two conditions potentially met by organ transplantation. This could explain why a significant proportion of transplant recipients develop DSA despite therapeutic immunosuppression. Using murine models, we confirmed that heart transplantation, but not skin grafting, is associated with accumulation of a high quantity of alloantigens in recipients' spleen. Nevertheless, neither naive nor memory DSA responses could be observed after transplantation of an allogeneic heart into recipients genetically deficient for CD4+ T cells. These findings suggest that DSA generation rather result from insufficient blockade of the helper function of CD4+ T cells by therapeutic immunosuppression. To test this second theory, different subsets of circulating T cells: CD8+, CD4+, and T follicular helper [CD4+ CXCDR5+, T follicular helper cells (Tfh)], were analyzed in 9 healthy controls and 22 renal recipients. In line with our hypothesis, we observed that triple maintenance immunosuppression (CNI + MMF + steroids) efficiently blocked activation-induced upregulation of CD25 on CD8+, but not on CD4+ T cells. Although the level of expression of CD40L and ICOS was lower on activated Tfh of immunosuppressed patients, the percentage of CD40L-expressing Tfh was the same than control patients, as was Tfh production of IL21. Induction therapy with antithymocyte globulin (ATG) resulted in prolonged depletion of Tfh and reduction of CD4+ T cells number with depleting monoclonal antibody in murine model resulted in exponential decrease in DSA titers. Furthermore, induction with ATG also had long-term beneficial influence on Tfh function after immune reconstitution. We conclude that CD4+ T cell help is mandatory for naive and memory DSA responses, making Tfh cells attractive targets for improving the prevention of DSA generation and to prolong allograft survival. Waiting for innovative treatments to be translated into the clinical field ATG induction seems to currently offer the best clinical prospect to achieve this goal.

Detection of alloreactive anti-HLA antibodies is a frequent and mandatory test before and after organ transplantation to determine the antigenic targets of the antibodies. Nowadays, this test involves the measurement of fluorescent signals generated through antibody–antigen reactions on multi-beads flow cytometers. In this study, in a cohort of 1,066 patients from one country, anti-HLA class I responses were analyzed on a panel of 98 different antigens. Knowing that the immune system responds typically to “shared” antigenic targets, we studied the clustering patterns of antibody responses against HLA class I antigens without any a priori hypothesis, applying two unsupervised machine learning approaches. At first, the principal component analysis (PCA) projections of intra-locus specific responses showed that anti-HLA-A and anti-HLA-C were the most distantly projected responses in the population with the anti-HLA-B responses to be projected between them. When PCA was applied on the responses against antigens belonging to a single locus, some already known groupings were confirmed while several new cross-reactive patterns of alloreactivity were detected. Anti-HLA-A responses projected through PCA suggested that three cross-reactive groups accounted for about 70% of the variance observed in the population, while anti-HLA-B responses were mainly characterized by a distinction between previously described Bw4 and Bw6 cross-reactive groups followed by several yet undocumented or poorly described ones. Furthermore, anti-HLA-C responses could be explained by two major cross-reactive groups completely overlapping with previously described C1 and C2 allelic groups. A second feature-based analysis of all antigenic specificities, projected as a dendrogram, generated a robust measure of allelic antigenic distances depicting bead-array defined cross reactive groups. Finally, amino acid combinations explaining major population specific cross-reactive groups were described. The interpretation of the results was based on the current knowledge of the antigenic targets of the antibodies as they have been characterized either experimentally or computationally and appear at the HLA epitope registry.

Background Hematopoietic stem and progenitor cells (HSPCs) mobilize from bone marrow to peripheral blood in response to stress. The impact of alloresponse-induced stress on HSPCs mobilization in human liver transplantation (LTx) recipients remains under-investigated. Methods Peripheral blood mononuclear cell (PBMC) samples were longitudinally collected from pre- to post-LTx for one year from 36 recipients with acute rejection (AR), 74 recipients without rejection (NR), and 5 recipients with graft-versus-host disease (GVHD). 28 PBMC samples from age-matched healthy donors were collected as healthy control (HC). Multi-color flow cytometry (MCFC) was used to immunophenotype HSPCs and their subpopulations. Donor recipient-distinguishable major histocompatibility complex (MHC) antibodies determined cell origin. Results Before LTx, patients who developed AR after transplant contained more HSPCs in PBMC samples than HC, while the NR group patients contained fewer HSPCs than HC. After LTx, the HSPC ratio in the AR group sharply decreased and became less than HC within six months, and dropped to a comparable NR level afterward. During the one-year follow-up period, myeloid progenitors (MPs) biased differentiation was observed in all LTx recipients who were under tacrolimus-based immunosuppressive treatment. During both AR and GVHD episodes, the recipient-derived and donor-derived HSPCs mobilized into the recipient’s blood-circulation and migrated to the target tissue, respectively. The HSPCs percentage in blood reduced after the disease was cured. Conclusions A preoperative high HSPC ratio in blood characterizes recipients who developed AR after LTx. Recipients exhibited a decline in blood-circulating HSPCs after transplant, the cells mobilized into the blood and migrated to target tissue during alloresponse.

The signal regulatory protein alpha (SIRPα)–CD47 axis regulates self-tolerance by delivering inhibitory signals to phagocytic cells and influencing immune responses in transplantation. This study examined the impact of SIRPα polymorphisms on CD47 binding capacity and T cell activation and analyzed the role of SIRPα genotypes in acute rejection following allogeneic liver transplantation. Peripheral blood mononuclear cells from healthy volunteers and data from liver transplant recipients were analyzed. Results showed that V2 SIRPα exhibited significantly higher CD47 binding capacity and enhanced costimulatory activity on CD4+ T cell proliferation compared V1 under both CD28− and CD28+ conditions, with further augmentation in the CD28+ setting. In the liver transplant cohort, SIRPα V2 was associated with higher acute rejection incidences than V1. These findings suggest that SIRPα polymorphisms, particularly V2, enhance T cell activation and modulate alloimmune responses through both innate and adaptive immunity, with potential implications for transplant outcomes. SIRPα genotyping may serve as one component within broader, multiparameter risk models for acute rejection and help inform optimization of immunosuppressive strategies.

Lipocalin-2 (Lcn2) is a sensitive early marker for acute kidney injury, delayed graft function and acute rejection of kidney transplants. We previously showed the renoprotective effect of recombinant Lcn2:Siderophore: Fe3 (rLcn2) in a mouse kidney transplantation (KTx) model. Here, we investigate the molecular and cellular mechanisms underlying these effects. Male C57BL/6 mice (10-12 weeks) received BALB/c kidney allografts, with or without rLcn2 treatment (250 µg, s.c.). To examine the immunomodulatory function of rLcn2, immune cells from graft, spleen, lymph nodes and blood were analyzed by flow cytometry at post-operative days (pod) 3 and 7. Syngeneic C57BL/6 grafts were used to investigate the impact of rLcn2 on alloimmune-independent tissue injury and inflammation through multiplex signaling assays, functional readouts, cytokine profiling and histopathological analyses. rLcn2 treatment markedly reduced frequencies of distinct T cell subsets, including effector memory T cells and their cytotoxic (T ) and helper (T ) subsets across grafts, lymphoid tissues and blood by pod-7 following allogeneic KTx. In graft infiltrating CD8 T cells, rLcn2 decreased degranulation capacity and diminished expression of interferon-γ and perforin. rLcn2 also lowered the proportion of NKG2D CD8 T cells, an activating T subset, in spleen and blood. In contrast, its impact on innate immune cells was modest and selective, influencing only neutrophils, macrophages in lymph nodes and intermediate mature NK cells in spleen and blood. No significant effect of rLcn2 treatment was observed on alloimmune-independent tissue injury or inflammation in syngeneic kidney grafts. rLcn2 selectively modulates T-cell activity after KTx without affecting alloimmune-independent injury pathways.

Current pre-transplantation routine matching involves serum anti-HLA antibodies quantification but cannot always preclude unfavorable graft outcomes. Epitope-based matching is proposed as a more precise approach, but to date no epitope-matching algorithm provides a satisfactory predictive tool for transplantation outcomes. In this study, anti-HLA-II loci responses from 1748 patients were analyzed with unsupervised machine learning algorithms, namely principal component analysis (PCA) and antigenic distances, projected as dendrograms. PCA for anti-HLA-DR anti-bodies revealed three main clusters of responses: anti-HLA-DR51 combined with anti-HLA-DRB1*01, anti-HLA-DR52 combined with anti-HLA-DRB1*08 and anti-HLA-DR53 combined with anti-HLA-DRB1*10. The dendrogram for anti-HLA-DR confirmed the pattern and showed further bisection of each cluster. Common epitopes present exclusively in all HLA molecules of each cluster were determined following the HLA epitope registry. Thus, we propose that 19 out of 123 HLA-DR epitopes are those that mainly lead anti-HLA-DR responses in the studied population. Likewise, we identified 22 out of 83 epitopes responsible for anti-HLA-DQ and 13 out of 62 responsible for anti-HLA-DP responses. Interpretation of these results may elucidate mechanisms of interlocus cross-reactivity, providing an alternative way of estimating the significance of each epitope in a population and thus suggesting a novel strategy towards optimal donor selection.