Browsing by Subject "Acute rejection"

Now showing 1 - 7 of 7
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    All that glitters in cfDNA analysis is not gold or its utility is completely established due to graft damage: a critical review in the field of transplantation
    (MDPI, 2023-06-06) Jiménez Coll, Víctor; El kaaoui El band, Jaouad; Llorente, Santiago; González López, Rosana; Fernández González, Marina; Martínez Banaclocha, Helios; Galián, José Antonio; Botella, Carmen; Moya Quiles, María Rosa; Minguela, Alfredo; Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    In kidney transplantation, a biopsy is currently the gold standard for monitoring the transplanted organ. However, this is far from an ideal screening method given its invasive nature and the discomfort it can cause the patient. Large-scale studies in renal transplantation show that approximately 1% of biopsies generate major complications, with a risk of macroscopic hematuria greater than 3.5%. It would not be until 2011 that a method to detect donor-derived cell-free DNA (dd-cfDNA) employing digital PCR was devised based on analyzing the differences in SNPs between the donor and recipient. In addition, since the initial validation studies were carried out at the specific moments in which rejection was suspected, there is still not a good understanding of how dd-cfDNA levels naturally evolve post-transplant. In addition, various factors, both in the recipient and the donor, can influence dd-cfDNA levels and cause increases in the levels of dd-cfDNA themselves without suspicion of rejection. All that glitters in this technology is not gold; therefore, in this article, we discuss the current state of clinical studies, the benefits, and disadvantages.
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    Computational prediction of biomarkers, pathways, and new target drugs in the pathogenesis of immune-based diseases regarding kidney transplantation rejection
    (Frontiers Media, 2021-12-15) Alfaro, Rafael; Martínez Banaclocha, Helios; Llorente, Santiago; Jiménez Coll, Víctor; Galián, José Antonio; Botella, Carmen; Moya Quiles, María Rosa; Parrado, Antonio; Muro Pérez, Manuel; Minguela, Alfredo; Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Background: The diagnosis of graft rejection in kidney transplantation (KT) patients is made by evaluating the histological characteristics of biopsy samples. The evolution of omics sciences and bioinformatics techniques has contributed to the advancement in searching and predicting biomarkers, pathways, and new target drugs that allow a more precise and less invasive diagnosis. The aim was to search for differentially expressed genes (DEGs) in patients with/without antibody-mediated rejection (AMR) and find essential cells involved in AMR, new target drugs, protein-protein interactions (PPI), and know their functional and biological analysis. Material and Methods: Four GEO databases of kidney biopsies of kidney transplantation with/without AMR were analyzed. The infiltrating leukocyte populations in the graft, new target drugs, protein-protein interactions (PPI), functional and biological analysis were studied by different bioinformatics tools. Results: Our results show DEGs and the infiltrating leukocyte populations in the graft. There is an increase in the expression of genes related to different stages of the activation of the immune system, antigenic presentation such as antibody-mediated cytotoxicity, or leukocyte migration during AMR. The importance of the IRF/STAT1 pathways of response to IFN in controlling the expression of genes related to humoral rejection. The genes of this biological pathway were postulated as potential therapeutic targets and biomarkers of AMR. These biological processes correlated showed the infiltration of NK cells and monocytes towards the allograft. Besides the increase in dendritic cell maturation, it plays a central role in mediating the damage suffered by the graft during AMR. Computational approaches to the search for new therapeutic uses of approved target drugs also showed that imatinib might theoretically be helpful in KT for the prevention and/or treatment of AMR. Conclusion: Our results suggest the importance of the IRF/STAT1 pathways in humoral kidney rejection. NK cells and monocytes in graft damage have an essential role during rejection, and imatinib improves KT outcomes. Our results will have to be validated for the potential use of overexpressed genes as rejection biomarkers that can be used as diagnostic and prognostic markers and as therapeutic targets to avoid graft rejection in patients undergoing kidney transplantation.
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    Donor-derived cell-free DNA in allograft transplantation: exaggerated hope or cautious reality?
    (MDPI, 2025-09-23) Fernández-González, Marina; Llorente, Santiago; Botella, Carmen; Galián, José Antonio; González-López, Rosana; Alegría-Marcos, María José; Hita, Alicia; Moya-Quiles, Rosa; Martínez-Banaclocha, Helios; Muro-Pérez, Manuel; Muro, Javier; Minguela, Alfredo; Legaz Pérez, Isabel; Muro, Manuel; Ciencias Sociosanitarias; Facultad de Química
    Nowadays, there have truly been spectacular advances in surgical techniques, the preservation of organs for transplants, the optimal and efficient selection of both donors and recipients, a more efficient diagnosis and prediction of possible complications of transplants, and important progress in the advances of pharmacological immunosuppression protocols and procedures. In this sense, survival rates after transplantation of various organs have been progressively increasing, especially in the case of lung transplants, whose average survival rate is usually lower than that of other types of solid organ transplants. Thus, detecting acute and subclinical rejection and chronic allograft rejection of any implant is important. This is important in all transplants, such as heart and lung transplants. In this last type of transplant, particularly, and due to the chronic dysfunction of the lung allograft, it is key to detect rejection early and on time, since it can reach close to half of the transplant patient population. Therefore, practical diagnostic tools are needed to visualize the level of allograft damage using genomic methods such as those that measure donor-derived cell-free DNA, where its amount increases in the plasma component of the transplant after tissue injury or due to allograft infection. This biomarker has become a key element with light and hope, but with some shadows of caution due to its use as a panacea. Our research team has experience in solid organ transplantation in quantifying this parameter in the progression of the lesion of the implanted allograft, and our experience and comparison with the published literature will be presented in the following review, discussing validated and non-validated results.
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    Early cytomegalovirus reactivation in renal recipients is associated with high levels of b cell maturation antigen transcript expression prior to transplantation
    (MDPI, 2023-06-22) Alfaro, Rafael; Rodríguez Aguilar, Luis; Llorente, Santiago; Jiménez Coll, Víctor; Martínez Banaclocha, Helios; Galián, José Antonio; Botella, Carmen; Moya Quiles, María Rosa; Muro Pérez, Manuel; Minguela, Alfredo; Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Cytomegalovirus (CMV) infection is the most frequent infection episode in kidney transplant (KT) recipients. Reactivation usually occurs in the first three months after transplantation and is associated with higher cellular and/or antibody-mediated rejection rates and poorer graft performance. CMV induces the expression of BAFF (B-cell-activating factor, a cytokine involved in the homeostasis of B cells), which communicates signals for survival and growth to B cells and virus-specific plasma cells via the R-BAFF (BAFF receptor), TACI (the calcium modulator, the cyclophilin ligand interactor), and BCMA (B cell maturation antigen) receptors. These molecules of the BAFF system have also been suggested as biomarkers for the development of alloantibodies and graft dysfunction. This prospective study included 30 CMV-IgG seropositive KT recipients. The expression levels of the genes BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA) in peripheral blood leukocytes (PBL) pre-KT were determined using qPCR. qPCR was also used to monitor CMV reactivation in the first three months following KT. The remainder of the KT recipients were classified as CMV− reactivation, and those with more than 500 copies/mL in at least one sample were classified as CMV+ reactivation. There were no discernible variations in the BAFF-R and TACI transcript expression levels. In the CMV+ group, we examined the relationship between the transcript levels and peak viremia. Peak viremia levels and BCMA transcript levels showed a strong correlation. BAFF-R and TACI expressions showed no measurable differences. In patients with early CMV reactivation, high BCMA receptor expression was associated with increased plasmablast, lymphocyte B cell class-switched levels (LBCS), and viral load. Our findings demonstrate that pre-KT BCMA transcript levels increased in KT recipients with early CMV reactivation. These transcript levels positively correlate with peak viremia and weakly with plasmablast and LBCS levels in PBLs.
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    Importance of human leukocyte antigen antibodies and leukocyte antigen/killer-cell immunoglobulin-like receptor genes in liver transplantation
    (Baishideng Publishing Group, 2023-02-07) Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Many mechanisms have been proposed to explain the hypothetical state of hepatic tolerance, which is described by eventual imbalances or deregulation in the balance of cytokines, mediators, effectors, and regulatory cells in the complex milieu of the liver. In this section, we will comment on the importance of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) as well as the compatibility and pairings of HLA and killer-cell immunoglobulin-like receptor (KIR) genotypes in the evolution of liver transplantation. Thus, HLA compatibility, viral infections, and HLA-C/KIR combinations have all been linked to liver transplant rejection and survival. There have been reports of increased risk of acute and chronic rejection with ductopenia, faster graft fibrosis, biliary problems, poorer survival, and even de novo autoimmune hepatitis when DSAs are present in the recipient. Higher mean fluorescence intensity (MFI) values of the DSAs and smaller graft size were associated with poorer patient outcomes, implying that high-risk patients with preformed DSAs should be considered for selecting the graft placed and desensitization methods, according to the investigators. Similarly, in a combined kidney-liver transplant, a pretransplant with a visible expression of several DSAs revealed that these antibodies were resistant to treatment. The renal graft was lost owing to antibody-mediated rejection (AMR). The HLA antigens expressed by the transplanted liver graft influenced antibody elimination. Pathologists are increasingly diagnosing AMR in liver transplants, and desensitization therapy has even been employed in situations of AMR, particularly in patients with DSAs in kidney-hepatic transplants and high-class II MFI due to Luminex. In conclusion, after revealing the negative impacts of DSAs with high MFI, pretransplant virtual crossmatch techniques may be appropriate to improve evolution; however, they may extend cold ischemia periods by requiring the donor to be typed.
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    KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury
    (Lippincott, Williams & Wilkins, 2013-04-27) López Álvarez, María R.; Campillo, José A.; Moya Quiles, María Rosa; Bolarín, José Miguel; Peña, Jesús de la; Salgado, Gema; García Alonso, Ana M.; Muro, Manuel; Miras, Manuel; Alonso, Clara; Álvarez López, María Rocio; Minguela, Alfredo; Gimeno Arias, Lourdes; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    Background. Killer immunoglobulin-like receptors (KIRs) bind human leukocyte antigen (HLA) class-I (HLA-I) ligands and regulate functions of natural killer cells and subsets of T cells. KIR/HLA-I interactions allow predicting natural killer cell alloreactivity in hematopoietic stem cell transplantation and in HLA-compatible kidney transplants, but its meaning in liver transplantation remains controversial. Methods. KIR and HLA genotypes were studied in 402 liver transplants, using sequence-specific oligonucleotides and primer methods. Recipients and donor KIRs, HLA-C genotypes, KIR gene mismatches (MMs) between recipient-donor pairs, and KIR/HLA-ligand combinations were analyzed in overall transplantations, in the acute rejection (AR; n=110) and non-AR (n=292) groups. Results. KIR gene MMs between recipients and donors, mainly in activating KIRs, and KIR2DL3 and KIR2DS1 of recipients in the presence of donor C2 ligands, significantly enhanced early AR rate (P<0.05), with KIR2DL3+ and KIR2DS1+ exhibiting a synergic effect in dependence of the donor C2 ligand number (χ2=7.662, P=0.022). KIR2DL3, KIR2DS1, and also KIR2DS4+ significantly influenced short-term graft survival, with a benefit for transplantations combining KIR2DL3+ recipients and donors having C1 ligands (log rank, P<0.019 at 1 year; hazards ratio [HR], 0.321; 95% confidence interval [CI], 0.107–0.962; P=0.042), whereas KIR2DS1+ and KIR2DS4+ recipients combined with donors lacking C1 ligands (C2/C2) exhibited a worse graft survival (log rank, P=0.035 at 6 months; HR, 7.713; 95% CI, 2.156–27.369; P=0.002 for KIR2DS1+; and log rank, P=0.006 at 1 year; HR, 3.794; 95% CI, 1.267–11.365; P=0.017 for KIR2DS4). Conclusions. This study shows that KIR gene-gene MMs increase AR and that KIRs/C ligands associated to AR and KIR2DS4+/C ligands also influence short-term graft survival.
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    Monitoring of soluble forms of BAFF System (BAFF, APRIL, sR-BAFF, sTACI and sBCMA) in kidney transplantation
    (Springer, 2022-09-22) Alfaro, Rafael; Llorente, Santiago; Martínez, Pedro; Jiménez Coll, Víctor; Martínez Banaclocha, Helios; Galián, José Antonio; Botella, Carmen; Moya Quiles, María Rosa; Peña Moral, Jesús de la; Minguela, Alfredo; Muro, Manuel; Legaz Pérez, Isabel; Ciencias Sociosanitarias
    BAFF system plays an essential role in B cells homeostasis and tolerance, although it has widely not been tested in transplantation with doubtful results. The main purpose was to study the BAFF soluble forms and their correlation with acute rejection (AR) and donor-specific antibodies production. Serum levels of BAFF, APRIL, and soluble forms of their receptors were analyzed in renal recipients with and without acute rejection (AR/NAR) appearance. All molecules were evaluated at pre- and post-transplantation. sTACI showed a significant correlation with BAFF and sR-BAFF levels, and sBCMA also showed a positive correlation with sAPRIL levels. A significant increase in sAPRIL levels in patients suffering AR was also found, and ROC curves analysis showed an AUC = 0.724, a concentration of 6.05 ng/ml (sensitivity: 66.7%; specificity: 73.3%), the best cutoff point for predicting AR. In the post-transplant dynamics of sAPRIL levels in the longitudinal cohort, we observed a significant decrease at 3 and 6 month post-transplantation compared to pretransplantation status. We also observed that recipients with high pre-transplant levels of sAPRIL generated antibodies earlier than those with lower sAPRIL levels, although their long-term post-transplantation was not different. Our results show that elevated serum levels of APRIL may be helpful as a biomarker for the diagnosis of AR, although the longitudinal study shows that it is not helpful as a prognostic biomarker.