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Muro M, Legaz I. Importance of human leukocyte antigen antibodies and leukocyte antigen/killer-cell immunoglobulin-like receptor genes in liver transplantation. World J Gastroenterol 2023; 29:766-772. [PMID: 36816626 PMCID: PMC9932425 DOI: 10.3748/wjg.v29.i5.766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/25/2022] [Accepted: 01/18/2023] [Indexed: 02/06/2023] Open
Abstract
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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Affiliation(s)
- Manuel Muro
- Immunology Service, University Clinical Hospital Virgen de la Arrixaca-Biomedical Research Institute of Murcia (IMIB), Murcia 30120, Spain
| | - Isabel Legaz
- Department of Legal and Forensic Medicine, Biomedical Research Institute (IMIB), Regional Campus of International Excellence “Campus Mare Nostrum,” Faculty of Medicine, University of Murcia, Murcia 30120, Spain
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The endless history or search for the true role of alloantibodies in liver transplantation. Clin Res Hepatol Gastroenterol 2021; 45:101544. [PMID: 33077392 DOI: 10.1016/j.clinre.2020.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 09/10/2020] [Indexed: 02/04/2023]
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Influence of Preformed Antibodies in Liver Transplantation. J Clin Med 2020; 9:jcm9030708. [PMID: 32151032 PMCID: PMC7141359 DOI: 10.3390/jcm9030708] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
The significance of human leukocyte antigen (HLA) matching and preformed donor-specific antibodies (DSAs) in liver transplantation remains unclear. The aim of this study was to analyze the presence of DSAs in a large cohort of 810 liver recipients undergoing liver transplant to determine the influence on acute (AR) or chronic liver rejection (CR), graft loss and allograft survival. DSAs were identified using complement dependent cytotoxicity crossmatch (CDC-CM) and multiplexed solid-phase-based flow cytometry assay (Luminex). CDC-CM showed that a 3.2% of liver transplants were positive (+CDC-CM) with an AR frequency of 19.2% which was not different from that observed in negative patients (-CDC-CM, 22.3%). Only two patients transplanted with +CDC-CM (7.6%) developed CR and suffered re-transplant. +CDC-CM patients showed a significantly lower survival rate compared to -CDC-CM patients (23.1% vs. 59.1%, p = 0.0003), developing allograft failure within the first three months (p < 0.00001). In conclusion, we have demonstrated a relationship between the presence of preformed DSAs and the low graft liver survival, indicating the important role and the potential interest of performing this analysis before liver transplantation. Our results could help to detect patients with an increased risk of graft loss, a better choice of liver receptors as well as the establishment of individualized immunosuppressive regimens.
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Lee H, Park KH, Park HS, Ryu JH, Lim J, Kim Y, Na GH, Kim DG, Oh EJ. Human Leukocyte Antigen-C Genotype and Killer Immunoglobulin-like Receptor-Ligand Matching in Korean Living Donor Liver Transplantation. Ann Lab Med 2017; 37:45-52. [PMID: 27834065 PMCID: PMC5107617 DOI: 10.3343/alm.2017.37.1.45] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 06/24/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The interaction between killer immunoglobulin-like receptors (KIRs) and HLA class I regulates natural killer (NK) cell cytotoxicity and function. The impact of NK cell alloreactivity through KIR in liver transplantation remains unelucidated. Since the frequency of HLA-C and KIR genotypes show ethnic differences, we assessed the impact of HLA-C, KIR genotype, or KIR-ligand mismatch on the allograft outcome of Korean liver allografts. METHODS One hundred eighty-two living donor liver transplant patients were studied. Thirty-five patients (19.2%) had biopsy-confirmed acute rejection (AR), and eighteen (9.9%) had graft failure. The HLA-C compatibility, KIR genotypes, ligand-ligand, and KIR-ligand matching was retrospectively investigated for association with allograft outcomes. RESULTS Homozygous C1 ligands were predominant in both patients and donors, and frequency of the HLA-C2 allele in Koreans was lower than that in other ethnic groups. Despite the significantly lower frequency of the HLA-C2 genotype in Koreans, donors with at least one HLA-C2 allele showed higher rates of AR than donors with no HLA-C2 alleles (29.2% vs 15.7%, P=0.0423). Although KIR genotypes also showed ethnic differences, KIR genotypes and the number of activating KIR/inhibitory KIR were not associated with the allograft outcome. KIR-ligand mismatch was expected in 31.6% of Korean liver transplants and had no impact on AR or graft survival. CONCLUSIONS This study could not confirm the clinical impact of KIR genotypes and KIR-ligand mismatch. However, we demonstrated that the presence of HLA-C2 allele in the donor influenced AR of Korean liver allografts.
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Affiliation(s)
- Hyeyoung Lee
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Ki Hyun Park
- Department of Biomedical Science, Graduate School, the Catholic University of Korea, Seoul, Korea
| | - Hye Sun Park
- Department of Biomedical Science, Graduate School, the Catholic University of Korea, Seoul, Korea
| | - Ji Hyeong Ryu
- Department of Biomedical Science, Graduate School, the Catholic University of Korea, Seoul, Korea
| | - Jihyang Lim
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Yonggoo Kim
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Gun Hyung Na
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Dong Goo Kim
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea
| | - Eun Jee Oh
- Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, Korea.
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Fahrner R, Dondorf F, Ardelt M, Settmacher U, Rauchfuss F. Role of NK, NKT cells and macrophages in liver transplantation. World J Gastroenterol 2016; 22:6135-6144. [PMID: 27468206 PMCID: PMC4945975 DOI: 10.3748/wjg.v22.i27.6135] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/25/2016] [Accepted: 06/15/2016] [Indexed: 02/07/2023] Open
Abstract
Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia-reperfusion injury are discussed in this review.
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Harmon C, Sanchez-Fueyo A, O'Farrelly C, Houlihan DD. Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance? Am J Transplant 2016; 16:751-7. [PMID: 26690302 DOI: 10.1111/ajt.13565] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 09/15/2015] [Accepted: 10/05/2015] [Indexed: 01/25/2023]
Abstract
Natural killer (NK) cells are highly heterogeneous innate lymphocytes with a diverse repertoire of phenotypes and functions. Their role in organ transplantation has been poorly defined due to conflicting clinical and experimental data. There is evidence that NK cells can contribute to graft rejection and also to tolerance induction. In most solid organ transplantation settings, the role of NK cells is only considered from the perspective of the recipient immune system. In contrast to other organs, the liver contains major resident populations of immune cells, particularly enriched with innate lymphocytes such as NK cells, NKT cells, and gamma-delta T cells. Liver transplantation therefore results in a unique meeting of donor and recipient immune systems. The unusual immune repertoire and tolerogenic environment of the liver may explain why this potentially inflammatory "meeting" often results in attenuated immune responses and reduced requirement for immunosuppression. Recent trials of immunosuppression withdrawal in liver transplant patients have identified NK cell features as possible predictors of tolerance. Here we propose that hepatic NK cells play a key role in the induction of tolerance post-liver transplant and examine potential mechanisms by which these cells influence liver transplant outcome.
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Affiliation(s)
- C Harmon
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - A Sanchez-Fueyo
- Institute of Liver Studies, King's College Hospital, London, UK
| | - C O'Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.,School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - D D Houlihan
- Liver Unit, St. Vincent's University Hospital, Dublin, Ireland
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Fosby B, Næss S, Hov JR, Traherne J, Boberg KM, Trowsdale J, Foss A, Line PD, Franke A, Melum E, Scott H, Karlsen TH. HLA variants related to primary sclerosing cholangitis influence rejection after liver transplantation. World J Gastroenterol 2014; 20:3986-4000. [PMID: 24744588 PMCID: PMC3983454 DOI: 10.3748/wjg.v20.i14.3986] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2014] [Revised: 02/11/2014] [Accepted: 03/07/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate influence of human leukocyte antigen (HLA) and killer immunoglobuline-like receptor (KIR) genotypes on risks of acute rejection (AR) after liver transplantation (LTX). METHODS In this retrospective study we included 143 adult donor-recipient pairs with a minimum of 6 mo follow-up after LTX for whom DNA was available from both donor and recipients. Clinical data, all early complications including episodes and severity of AR and graft/patient survival were registered. The diagnosis of AR was based on clinical, biochemical and histological criteria. All suspected episodes of AR were biopsy confirmed. Key classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped using Sanger sequencing. 16 KIR genes were genotyped using a novel real time PCR approach which allows for determination of the diploid copy number of each KIR gene. Immunohistochemical staining for T (CD3), B (CD20) and natural killer (NK) cells (CD56 and CD57) were performed on liver biopsies from 3 different patient groups [primary sclerosing cholangitis (PSC), primary biliary cirrhosis and non-autoimmune liver disease], 10 in each group, with similar grade of AR. RESULTS Fourty-four (31%) patients were transplanted on the basis of PSC, 40% of them had AR vs 24% in the non-PSC group (P = 0.04). No significant impact of donor-recipient matching for HLA and KIR genotypes was detected. In the overall recipient population an increased risk of AR was detected for HLA-B*08 (P = 0.002, OR = 2.5; 95%CI: 1.4-4.6), HLA-C*07 (P = 0.001, OR = 2.4; 95%CI: 1.4-4.0) and HLA-DRB1*03 (P = 0.03, OR = 1.9; 95%CI: 1.0-3.3) and a decreased risk for HLA-DRB1*04 (P = 0.001, OR = 0.2; 95%CI: 0.1-0.5). For HLA-B*08, HLA-C*07 and DRB1*04 the associations remained evident in a subgroup analysis of non-PSC recipients (P = 0.04, P = 0.003 and P = 0.02, respectively). In PSC recipients corresponding P values were 0.002, 0.17 and 0.01 for HLA-B*08, HLA-C*07 and DRB1*04, respectively. A dosage effect of AR prevalence according to the PSC associated HLA alleles was also notable in the total recipient population. For HLA-B*08 the frequency of AR was 56% in HLA-B*08 homozygous recipients, 39% in heterozygous recipients and 21% in recipients lacking HLA-B*08 (P = 0.02). The same was observed for the HLA-C*07 allele with AR in 57%, 27% and 18% in recipients being homozygous, heterozygous and lacking HLA-C*07 respectively (P = 0.003). Immunohistochemical analysis showed similar infiltration of T, B and NK cells in biopsies with AR in all three groups. CONCLUSION We found significant associations between the PSC-associated HLA-B*08, HLA-C*07, HLA-DRB1*03 and HLA-DRB1*04 alleles and risk of AR in liver transplant recipients.
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KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury. Transplantation 2013; 95:1037-44. [PMID: 23478359 DOI: 10.1097/tp.0b013e318286486c] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
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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Saxena V, Lai JC, O'Leary JG, Verna EC, Brown RS, Stravitz RT, Trotter JF, Krishnan K, Terrault NA, the ConsoRtiUm to Study Health Outcomes in HCV Liver Transplant Recipients (CRUSH-C). Recipient-donor race mismatch for African American liver transplant patients with chronic hepatitis C. Liver Transpl 2012; 18:524-31. [PMID: 22140019 PMCID: PMC3314141 DOI: 10.1002/lt.22461] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
African American (AA) recipient-donor race mismatch has been associated with graft loss and mortality, but studies of an association between race mismatch and hepatitis C virus (HCV) disease severity are lacking. HCV-infected adults from 4 US centers who underwent liver transplantation for the first time (n = 1093) were followed for a median of 3.05 years to determine the rates of advanced HCV disease (bridging fibrosis or cirrhosis) and graft failure; 11% of the patients were AA. The unadjusted cumulative rate of advanced fibrosis was higher in AAs than non-AAs (56% and 40% at 4 years, respectively, (P < 0.01), and 59% and 56% for AA recipient-donor-matched patients and AA recipient-donor-mismatched patients, respectively (P = 0.89). In adjusted models, both AA recipient race [hazard ratio (HR) = 1.47, 95% CI = 1.06-2.03, P = 0.02] and AA recipient-donor mismatch (versus match; HR = 1.48, 95% CI = 1.03-2.12, P = 0.03) were significant predictors of advanced fibrosis; other independent predictors were donor age (HR = 1.21, P < 0.01) and cytomegalovirus infection (HR = 1.55, P < 0.01). The 4-year unadjusted cumulative rates for HCV-associated graft loss were 10% and 17% for non-AAs and AAs, respectively (P < 0.01), and 0% and 21% for AA recipient-donor-matched patients and AA recipient-donor-mismatched patients, respectively (P < 0.01). In adjusted models, AA recipient-donor-mismatched patients had a 62% higher rate of graft loss than non-AA recipients (HR = 1.62, 95% CI = 1.14-2.29, P < 0.01), and AA recipient-donor-matched patients had a 76% lower rate of graft loss/mortality (HR = 0.24, 95% CI = 0.06-0.97, P = 0.05). In conclusion, AA recipient-donor-mismatched patients who are infected with HCV are at high risk for advanced HCV disease and HCV-related graft loss and constitute a patient group that will benefit from new therapeutic strategies for preventing graft loss.
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Affiliation(s)
- Varun Saxena
- Department of Medicine, University of California San Francisco
| | - Jennifer C. Lai
- Department of Medicine, University of California San Francisco
| | | | | | - Robert S. Brown
- Department of Medicine, New York Presbyterian Hospital-Columbia
| | - R. Todd Stravitz
- Department of Medicine, Virginia Commonwealth University Medical Center
| | - James F. Trotter
- Baylor Simmons Transplant Institute, Baylor University Medical Center, Dallas
| | - Kartik Krishnan
- Department of Medicine, University of California San Francisco
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Muro M, López-Álvarez MR, Campillo JA, Marin L, Moya-Quiles MR, Bolarín JM, Botella C, Salgado G, Martínez P, Sánchez-Bueno F, López-Hernández R, Boix F, Bosch A, Martínez H, de la Peña-Moral JM, Pérez N, Robles R, García-Alonso AM, Minguela A, Miras M, Alvarez-López MR. Influence of human leukocyte antigen mismatching on rejection development and allograft survival in liver transplantation: is the relevance of HLA-A locus matching being underestimated? Transpl Immunol 2012; 26:88-93. [PMID: 22129495 DOI: 10.1016/j.trim.2011.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 11/14/2011] [Accepted: 11/14/2011] [Indexed: 11/28/2022]
Abstract
The influence of HLA matching on liver transplant is still controversial, as studies have failed to demonstrate an adverse effect of HLA mismatching on transplant outcome. We examined the effect of HLA mismatching on transplant outcome in a series of 342 consecutive liver transplants (224 finally analyzed). HLA typing was performed by serological and molecular methods. HLA-A matching was associated with an increased chronic rejection incidence (P=0.04). Indeed, HLA-A match also demonstrated a significant impact on allograft survival (P=0.03), confirming previous observation concerning to rejection, as complete HLA-A mismatching favored a better liver transplant outcome. Analysis of HLA-A+B+DR matching also demonstrated a significant impact on graft survival (P<0.05). Multivariate Cox regression analysis confirmed the effect of HLA-A and DPB1 matching as independent risk factors for graft loss. Another independent factor was a positive pre-transplant crossmatch. In conclusion, liver transplant outcome has not been found to be improved by HLA matching, however a poorer HLA compatibility favored a better graft survival and decreased rejection incidence, with a special relevance for HLA-A matching.
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Affiliation(s)
- Manuel Muro
- Immunology Service, University Hospital Virgen Arrixaca, Murcia 30120, Spain.
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Morice A, Charreau B, Neveu B, Brouard S, Soulillou JP, Bonneville M, Houssaint E, Degauque N. Cross-reactivity of herpesvirus-specific CD8 T cell lines toward allogeneic class I MHC molecules. PLoS One 2010; 5:e12120. [PMID: 20711433 PMCID: PMC2920819 DOI: 10.1371/journal.pone.0012120] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Accepted: 07/19/2010] [Indexed: 12/02/2022] Open
Abstract
Although association between persistent viral infection and allograft rejection is well characterized, few examples of T-cell cross-reactivity between self-MHC/viral and allogeneic HLA molecules have been documented so far. We appraised in this study the alloreactivity of CD8 T cell lines specific for immunodominant epitopes from human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). CD8 T cell lines were generated after sorting with immunomagnetic beads coated with either pp65495–503/A*0201, BMLF1259–267/A*0201, or BZLF154–64/B*3501 multimeric complexes. Alloreactivity of the CD8 T cell lines against allogeneic class I MHC alleles was assessed by screening of (i) TNF-α production against COS-7 cells transfected with as many as 39 individual HLA class I-encoding cDNA, and (ii) cytotoxicity activity toward a large panel of HLA-typed EBV-transformed B lymphoblastoid cell lines. We identified several cross-reactive pp65/A*0201-specific T cell lines toward allogeneic HLA-A*3001, A*3101, or A*3201. Moreover, we described here cross-recognition of HLA-Cw*0602 by BZLF1/B*3501-specific T cells. It is noteworthy that these alloreactive CD8 T cell lines showed efficient recognition of endothelial cells expressing the relevant HLA class I allele, with high level TNF-α production and cytotoxicity activity. Taken together, our data support the notion that herpes virus-specific T cells recognizing allo-HLA alleles may promote solid organ rejection.
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Affiliation(s)
- Alexis Morice
- UMR892, INSERM - Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France
| | | | - Bérangère Neveu
- UMR892, INSERM - Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France
| | - Sophie Brouard
- UMR 643, INSERM, Nantes, France
- ITUN, CHU Nantes, Nantes, France
- Faculté de Médecine, Université de Nantes, Nantes, France
| | - Jean-Paul Soulillou
- UMR 643, INSERM, Nantes, France
- ITUN, CHU Nantes, Nantes, France
- Faculté de Médecine, Université de Nantes, Nantes, France
| | - Marc Bonneville
- UMR892, INSERM - Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France
| | - Elisabeth Houssaint
- UMR892, INSERM - Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France
- Faculté des Sciences, Université de Nantes, Nantes, France
| | - Nicolas Degauque
- UMR 643, INSERM, Nantes, France
- ITUN, CHU Nantes, Nantes, France
- Faculté de Médecine, Université de Nantes, Nantes, France
- * E-mail:
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Lan X, Zhang MM, Pu CL, Guo CB, Kang Q, Li YC, Dai XK, Deng YH, Xiong Q, Ren ZM. Impact of human leukocyte antigen mismatching on outcomes of liver transplantation: A meta-analysis. World J Gastroenterol 2010; 16:3457-64. [PMID: 20632452 PMCID: PMC2904896 DOI: 10.3748/wjg.v16.i27.3457] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To assess the effect of human leukocyte antigen (HLA) mismatching on liver graft outcome and acute rejection from a meta-analysis of available cohort studies.
METHODS: Articles in PubMed/MEDLINE, EMBASE and the Cochrane database from January 1970 to June 2009, including non-English literature identified in these databases, were searched. Only studies comparing HLA or sub-phenotype matching with mismatching were extracted. The percentage of graft survival was extracted by “Engauge Digitizer” from survival curves if the raw data were not displayed. A meta-analysis was performed when at least 3 studies provided data.
RESULTS: Sixteen studies met the inclusion criteria. A lower number of HLA mismatches (0-2 vs 3-6) did reduce the incidence of acute rejection (relative risk: 0.77, P = 0.03). The degree of HLA mismatching (0-2 vs 3-6) had no significant effect on 1-year [hazard ratio (HR): 1.04, P = 0.68] and 5-year (HR: 1.09, P = 0.38) graft survival. In sub-phenotype analysis, the degree of HLA-A, B and DR mismatching (0 vs 1-2) had no significant effect on 1-year and 5-year graft survival, either. The HRs and P-values were 0.95, 0.71 (HLA-A, 1-year); 1.06, 0.60 (HLA-A, 5-year); 0.77, 0.16 (HLA-B, 1-year); 1.07, 0.56 (HLA-DR, 1-year); 1.18, 0.23 (HLA-DR, 5-year), respectively.
CONCLUSION: The results of this systematic review imply that good HLA compatibility can reduce the incidence of acute rejection in spite of having no influence on graft outcomes. To obtain a short recovery time and minimize rejection post transplantation, HLA matching studies should be considered before the operation.
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Kim SJ, Kim DG, Kim TG, Choi HB, Jung ES. Recipient's Killer Cell Immunoglobulin-like Receptor Genotype and Human Leukocyte Antigen C Ligand Influence the Clinical Outcome following Living Donor Liver Transplantation. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2010. [DOI: 10.4174/jkss.2010.78.6.357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Say-June Kim
- Department of Surgery, Daejeon St. Mary's Hospital, The Catholic University of Korea, School of Medicine, Daejeon, Korea
| | - Dong-Goo Kim
- Department of Surgery, Seoul St. Mary's Hospital, The Catholic University of Korea, School of Medicine, Seoul, Korea
| | - Tai-Gyu Kim
- Department of Microbiology, Seoul St. Mary's Hospital, The Catholic University of Korea, School of Medicine, Seoul, Korea
| | - Hee-Baeg Choi
- Hematopoietic Stem Cell Bank, Seoul St. Mary's Hospital, The Catholic University of Korea, School of Medicine, Seoul, Korea
| | - Eun-Sun Jung
- Department of Pathology, Seoul St. Mary's Hospital, The Catholic University of Korea, School of Medicine, Seoul, Korea
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14
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HLA-C Matching and Liver Transplants: Donor-Recipient Genotypes Influence Early Outcome and CD8+KIR2D+ T-Cells Recuperation. Transplantation 2009; 88:S54-61. [DOI: 10.1097/tp.0b013e3181af7d84] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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15
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de Arias AE, Haworth SE, Belli LS, Burra P, Pinzello G, Vangeli M, Minola E, Guido M, Boccagni P, De Feo TM, Torelli R, Cardillo M, Scalamogna M, Poli F. Killer cell immunoglobulin-like receptor genotype and killer cell immunoglobulin-like receptor-human leukocyte antigen C ligand compatibility affect the severity of hepatitis C virus recurrence after liver transplantation. Liver Transpl 2009; 15:390-9. [PMID: 19326408 DOI: 10.1002/lt.21673] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
In 20% to 30% of infected individuals, hepatitis C virus (HCV) can cause cirrhosis and hepatocellular carcinoma, for which liver transplantation is the best treatment available. HCV re-infection is universal, and hepatitis disease recurrence occurs in most cases with a 30% probability of progression to graft cirrhosis at 5 years post-transplant. The immunological response to HCV involves natural killer (NK) cells and killer cell immunoglobulin-like receptors (KIRs), which specifically recognize human leukocyte antigen (HLA) class I antigens present on target cells. The effector functions of NK cells are influenced by inhibitory KIR interaction with self-HLA class I ligands, with HLA-C being the most predominant. This study examines the roles of KIR genotypes and their HLA ligands in both HCV disease recurrence and its progression. A total of 151 patients were included in the cohort, and their clinical details were recorded. Liver biopsies were used to define the absence/presence of recurrent hepatitis, the degree of fibrosis, and the progression to cirrhosis over a 10-year period. Mismatching of KIR-HLA-C ligands between donor-recipient pairs was associated with the recurrence of hepatitis (P = 0.008). The presence of KIR2DL3 in the recipient correlated with progression to liver fibrosis (P = 0.04). The mismatching of HLA-KIR ligands favored the progression of the recurrent hepatitis to fibrosis only in the presence of KIR2DL3 (P = 0.04). These preliminary results indicate that the KIR genotype and KIR-HLA-C ligand compatibility play roles in the recurrence and progression of hepatitis C disease in liver transplant recipients.
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Affiliation(s)
- Alejandro Espadas de Arias
- Department of Regenerative Medicine, Organ and Tissue Transplantation Immunology, Ospedale Maggiore Policlinico, Mangiagalli, Regina Elena, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
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16
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Muro M, Rojas G, Botella C, Miras M, Campillo JA, Minguela A, Sánchez-Bueno F, Bermejo J, Ramírez P, Álvarez-López MR. CT60 A/G marker of the 3′-UTR of the CTLA4 gene and liver transplant. Transpl Immunol 2008; 18:246-9. [DOI: 10.1016/j.trim.2007.07.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2007] [Accepted: 07/16/2007] [Indexed: 11/16/2022]
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17
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Natural killer cell subsets in allograft rejection and tolerance. Curr Opin Organ Transplant 2007; 12:10-16. [PMID: 27792083 DOI: 10.1097/mot.0b013e3280129f2a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To discuss the role of natural killer cells in regulating the survival of transplanted organs. RECENT FINDINGS Natural killer cells have been found to have the dual capacity to promote rejection of transplanted organs and be required for the induction of transplantation tolerance. In murine recipients of bone marrow transplants, or in CD28 recipients of cardiac allografts, different natural killer cell subsets have been shown to promote or delay rejection, depending on their major histocompatibility complex class I specificity. In mouse models of skin and islet allograft acceptance mediated by costimulation-targeting therapies, the presence of natural killer cells was found to be essential for long-term graft acceptance, perhaps due to their ability to eliminate donor or recipient immune cells. SUMMARY Natural killer cells can either accelerate or avert rejection in a manner that is influenced by both donor-recipient major histocompatibility complex disparity as well as the milieu created by costimulation-targeting therapies. In clinical settings, alloreactivity by defined natural killer cell subsets may be important in achieving tolerance, and the outcome of natural killer cell activity may be influenced by specific immunosuppressive regimens.
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18
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Moya-Quiles MR, Alvarez R, Miras M, Gomez-Mateo J, Lopez-Alvarez MR, Marin-Moreno I, Martínez-Barba E, Sanchez-Mozo MPS, Gomez M, Arnal F, Sanchez-Bueno F, Marin LA, Garcia-Alonso AM, Minguela A, Muro M, Parrilla P, Alonso C, Alvarez-López MR. Impact of recipient HLA-C in liver transplant: a protective effect of HLA-Cw*07 on acute rejection. Hum Immunol 2006; 68:51-8. [PMID: 17207712 DOI: 10.1016/j.humimm.2006.10.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Revised: 10/05/2006] [Accepted: 10/13/2006] [Indexed: 01/09/2023]
Abstract
The involvement of the human leukocyte antigen (HLA) in liver graft acceptance is controversial, but the frequency of acute rejection (AR) remains high in spite of the use of the modern immunosuppressive agents. The present study was aimed at determining whether an association exists between liver recipient HLA-C polymorphism and AR development that could influence graft acceptance. Four hundred and forty-six liver recipients and 473 controls were studied within the framework of a collaborative study carried out by the Spanish Transplant Immunotolerance Group (RED-GIT). HLA-A and -B were typed by the standard microlymphocytotoxicity technique, and HLA-C by polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP). A statistically significant decrease in the HLA-Cw*07 allele frequency was found in liver recipients suffering AR episodes compared to those without AR (NAR). Studies regarding the possible influence of the Asn80 and Lys80 epitopes showed that the Asn80 epitope also could be associated with AR. However, further analysis considering Asn80 alleles others than HLA-Cw*07, confirmed that the apparent protective effect of the Asn80 epitope was actually from the HLA-Cw*07 allele. In conclusion, the HLA-Cw*07 allele carried by the liver recipient is negatively associated with AR development, and could be considered a predictive factor for liver graft acceptance.
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Affiliation(s)
- Maria R Moya-Quiles
- Immunology Service, University Hospital Virgen de la Arrixaca, 30120 El Palmar, Murcia, Spain
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19
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Montes-Ares O, Moya-Quiles MR, Montes-Casado M, Guerra-Pérez N, Campillo JA, González C, López-Bermejo A, Tamayo M, Majado MJ, Parrado A, Muro M, Marín L, Alvarez-López MR. Human leucocyte antigen-C in B chronic lymphocytic leukaemia. Br J Haematol 2006; 135:517-9. [PMID: 17054674 DOI: 10.1111/j.1365-2141.2006.06334.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
This study aimed at characterising the distribution of human leucocyte antigen (HLA)-C alleles in a large group of patients with B chronic lymphocytic leukaemia from Southeastern Spain. Ninety-eight adult patients and 194 geographically and ethnically matched controls were studied. HLA-C was determined by polymerase chain reaction sequence-specific primers (PCR-SSP) and PCR-sequence-specific oligonucleotides (SSO) methods. The HLA-Cw*16 allele frequency was found to be significantly increased amongst patients compared with controls in our population (27.6% vs. 12.4%, P = 0.0012, Pc = 0.016). HLA-C dimorphism was also analysed but no association was found.
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Affiliation(s)
- Olga Montes-Ares
- Department of Immunology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
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20
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López-Alvarez MR, Gómez-Mateo J, Ruiz-Merino G, Campillo JA, Miras M, García-Alonso AM, Sánchez-Bueno F, Parrilla P, Alvarez-López MR, Minguela A. Analysis of KIR2D receptors on peripheral blood lymphocytes from liver graft recipients. Transpl Immunol 2006; 17:51-4. [PMID: 17157216 DOI: 10.1016/j.trim.2006.09.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2006] [Accepted: 09/13/2006] [Indexed: 02/08/2023]
Abstract
KIR2D receptors are killer cell immunoglobulin-like receptors (KIRs) specific for HLA-C epitopes, that are expressed on NK cells as well as on minor peripheral blood T-cell subsets, and are able to control NK and T cells activity. The present work explores NK, and particularly CD8(+) T cells expressing KIR2D2L1/S1 (CD158a) or KIR2D2L2/3/S2 (CD158b) receptors in liver graft alloresponse. Flow cytometry was used to analyse peripheral blood mononuclear cells stained with anti-CD158a and anti-CD158b antibodies from 110 liver recipients and 46 healthy controls, previous to and along the first month after transplantation. Pre-transplantation data shows that both CD158a and CD158b molecules can be detected on NK and T cells from all patients and controls, but both KIR2D(+)NK cells are significantly under-represented in patients respect to controls (P<0.001), and CD3(+)CD8(+)CD158a(+) cells decreased particularly in patients suffering from acute rejection (4.03+/-1.33 cells/microL) compared with controls (7.8+/-2.4 cells/microL). Following transplantation, KIR2D(+)CD8(+) T-cell repertoires increased through the first month, mainly in recipients with a good graft acceptance. In summary, monitoring of KIR2D(+)CD8(+) T cells, particularly KIR2DL1/S1(+)CD8(+) T cells at pre-transplant, and both KIR2DL1/S1(+) and KIR2DL2/3/S2(+) T-cell subsets at early post-transplant period, could offer useful information for clinical follow-up of liver grafts.
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Affiliation(s)
- María R López-Alvarez
- Immunology Service, Hospital Universitario Virgen de la Arrixaca, 30120 Murcia, Spain
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21
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Minguela A, Miras M, Bermejo J, Sánchez-Bueno F, López-Alvarez MR, Moya-Quiles MR, Muro M, Ontañón J, Garía-Alonso AM, Parrilla P, Alvarez-López MR. HBV and HCV infections and acute rejection differentially modulate CD95 and CD28 expression on peripheral blood lymphocytes after liver transplantation. Hum Immunol 2006; 67:884-93. [PMID: 17145368 DOI: 10.1016/j.humimm.2006.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Revised: 06/20/2006] [Accepted: 06/29/2006] [Indexed: 12/21/2022]
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) generally reinfect liver graft early posttransplantation and lead to poorer graft and patient survivals. In the present study the influence of acute rejection (AR), HBV and HCV infections, and human leukocyte antigen (HLA) class-I compatibility on the expression of CD28 (in 237 liver recipients) and CD95 (in 114 liver recipients) on peripheral blood cells were evaluated by flow cytometry during the first month after transplantation. HBV/HCV infections induced strong CD95 upregulation on CD3+ lymphocytes. Maximal CD95 upmodulation was found in infected recipients showing partial HLA class-I compatibility. AR and virus reinfection could be distinguished because CD28 was upregulated on CD4+ lymphocytes only in recipients with AR, irrespective of their status regarding HBV/HCV infections. In conclusion, cytometric co-evaluation of CD95 and CD28 expression on peripheral blood lymphocytes could be useful to discriminate AR from cellular activation induced by viral reinfection of the liver graft.
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Affiliation(s)
- Alfredo Minguela
- Immunology Services, Virgen de la Arrixaca University Hospital, Murcia, Spain.
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22
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Bishara A, Brautbar C, Zamir G, Eid A, Safadi R. Impact of HLA-C and Bw epitopes disparity on liver transplantation outcome. Hum Immunol 2006; 66:1099-105. [PMID: 16571410 DOI: 10.1016/j.humimm.2005.10.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2005] [Revised: 09/10/2005] [Accepted: 10/10/2005] [Indexed: 01/09/2023]
Abstract
The occurrence of graft rejection episodes after orthotopic liver transplantation (OLT) despite the use of immunosuppressive drugs designed to suppress T lymphocyte functions, indicates the involvement of other types of cells in this process. The activity of natural killer cells and their killer immunoglobulin-like receptors (KIR) is regulated by human leukocyte antigen (HLA) class I determinants; C and Bw epitopes. Because recipient/donor pairs are usually HLA mismatched, recipient natural killer alloreactivity may be the mediating factor in rejection. In this retrospective study, we have analyzed rejection occurrence and outcome in 66 OLT recipients, 42 with and 24 without C or Bw epitope disparity in the rejection direction. Recipients transplanted from donors with no C epitope disparity had significantly fewer rejection episodes in the first year after transplantation compared with recipients transplanted across C epitope disparity (p = 0.0002). Moreover, this effect was more pronounced when the outcome was analyzed in OLT recipients across negative crossmatching for the anti-HLA class I and II antibodies. In contrast, Bw epitope disparity did not affect the outcome. In conclusion, C epitopes disparity between recipients and donors in the rejection direction appears to influence posttransplant liver outcome. This finding may be helpful in the choice of appropriate liver donor and planning immune suppression.
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Affiliation(s)
- Amal Bishara
- Tissue Typing Unit, Division of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
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23
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Muro M, Marin L, Miras M, Moya-Quiles R, Minguela A, Sánchez-Bueno F, Bermejo J, Robles R, Ramírez P, García-Alonso A, Parrilla P, Alvarez-López MR. Liver recipients harbouring anti-donor preformed lymphocytotoxic antibodies exhibit a poor allograft survival at the first year after transplantation: experience of one centre. Transpl Immunol 2005; 14:91-97. [PMID: 15935299 DOI: 10.1016/j.trim.2005.03.013] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2005] [Accepted: 03/28/2005] [Indexed: 12/20/2022]
Abstract
In this retrospective study, we analyzed the effect of the presence of anti-donor preformed alloantibodies in 268 liver allograft transplants. Crossmatches were performed by complement-dependent cytotoxicity (CDC) assay and HLA antibody screening by flow cytometry (FlowPRA). Positive anti-donor crossmatch was detected in 5.2% of transplants. Acute rejection frequency in +CDC crossmatch patients was not different from that observed in -CDC crossmatch patients. None of the patients transplanted with +CDC crossmatch developed chronic rejection, but they showed a significantly lower allograft survival rate, and the majority of them had allograft failures before the end of the first post-transplant year, mainly within the 3 first months. Indeed, positive FlowPRA determination was concordant with data from the CDC assay. In conclusion, these findings show a direct correlation between the presence of anti-donor preformed antibodies and a poor allograft survival in liver transplant.
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Affiliation(s)
- Manuel Muro
- Immunology Service, University Hospital Virgen de la Arrixaca, Murcia 30120, Spain.
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