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A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276.

ABSTRACT: BACKGROUND:Liver transplantation is an effective therapy for end-stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell-mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TREML2 with acute rejection, and evaluating its prognostic value of acute rejection after liver transplantation. METHODS:The study enrolled a total of 388 recipients. Among them, acute allograft rejection was observed in 54 cases. We performed single nucleotide polymorphism genotyping of CD276, including rs11072431, rs11574495, rs12593558, rs12594627, rs2127015, rs3816661 and rs7176654, and TREML2, including rs4714431, rs6915083, rs7754593, and rs9394767 from preoperative peripheral blood genome DNA. RESULTS:We found rs2127015 of CD276, rs6915083 and rs7754593 of TREML2, and HBV infection as well were associated with acute rejection. And, rs2127015 influences CD276 expression. Moreover, we established a risk assessment model, composited by statistically proved risk factors. CONCLUSION:By integrating both clinical and genetic variables, liver transplant recipients can be categorized into different risk groups, and might benefit from individualized therapies.

SUBMITTER: Yu X

PROVIDER: S-EPMC6603397 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276.

Yu Xiaobo X Wei Bajin B Su Rong R Yao Jia J Feng Xiaowen X Jiang Guoping G Xie Haiyang H Wu Jian J Xu Xiao X Zhang Min M Zheng Shusen S Zhou Lin L

Molecular genetics & genomic medicine 20190501 6

<h4>Background</h4>Liver transplantation is an effective therapy for end-stage liver diseases and acute liver failure. After the operation, however, recipients may suffer grafts loss induced by alloimmune reaction, which is termed as acute allograft rejection. The interaction between costimulatory molecules, CD276, and its ligand, TREML2, promotes T cell-mediated immune response, as well as acute or chronic allograft rejection. Our research aimed at correlating genetic polymorphisms of CD276/TRE ...[more]

PMID: 31044564

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Project description:Importance:Early allograft dysfunction (EAD) following a liver transplant (LT) unequivocally portends adverse graft and patient outcomes, but a widely accepted classification or grading system is lacking. Objective:To develop a model for individualized risk estimation of graft failure after LT and then compare the model's prognostic performance with the existing binary EAD definition (bilirubin level of ≥10 mg/dL on postoperative day 7, international normalized ratio of ≥1.6 on postoperative day 7, or aspartate aminotransferase or alanine aminotransferase level of >2000 U/L within the first 7 days) and the Model for Early Allograft Function (MEAF) score. Design, Setting, and Participants:This retrospective single-center analysis used a transplant database to identify all adult patients who underwent a primary LT and had data on 10 days of post-LT laboratory variables at the Dumont-UCLA Transplant Center of the David Geffen School of Medicine at UCLA between February 1, 2002, and June 30, 2015. Data collection took place from January 4, 2016, to June 30, 2016. Data analysis was conducted from July 1, 2016, to August 30, 2017. Main Outcomes and Measures:Three-month graft failure-free survival. Results:Of 2021 patients who underwent primary LT over the study period, 2008 (99.4%) had available perioperative data and were included in the analysis. The median (interquartile range [IQR]) age of recipients was 56 (49-62) years, and 1294 recipients (64.4%) were men. Overall survival and graft-failure-free survival rates were 83% and 81% at year 1, 74% and 71% at year 3, and 69% and 65% at year 5, with an 11.1% (222 recipients) incidence of 3-month graft failure or death. Multivariate factors associated with 3-month graft failure-free survival included post-LT aspartate aminotransferase level, international normalized ratio, bilirubin level, and platelet count, measures of which were used to calculate the Liver Graft Assessment Following Transplantation (L-GrAFT) risk score. The L-GrAFT model had an excellent C statistic of 0.85, with a significantly superior discrimination of 3-month graft failure-free survival compared with the existing EAD definition (C statistic, 0.68; P < .001) and the MEAF score (C statistic, 0.70; P < .001). Compared with patients with lower L-GrAFT risk, LT recipients in the highest 10th percentile of L-GrAFT scores had higher Model for End-Stage Liver Disease scores (median [IQR], 34 [26-40] vs 31 [25-38]; P = .005); greater need for pretransplant hospitalization (56.8% vs 44.8%; P = .003), renal replacement therapy (42.9% vs 30.5%; P < .001), mechanical ventilation (35.8% vs 18.1%; P < .001), and vasopressors (22.9% vs 11.0%; P < .001); longer cold ischemia times (median [IQR], 436 [311-539] vs 401 [302-506] minutes; P = .04); greater intraoperative blood transfusions (median [IQR], 17 [10-26] vs 10 [6-17] units of packed red blood cells; P < .001); and older donors (median [IQR] age, 47 [28-56] vs 41 [25-52] years; P < .001). Conclusions and Relevance:The L-GrAFT risk score allows a highly accurate, individualized risk estimation of 3-month graft failure following LT that is more accurate than existing EAD and MEAF scores. Multicenter validation may allow for the adoption of the L-GrAFT as a tool for evaluating the need for a retransplant, for establishing standardized grading of early allograft function across transplant centers, and as a highly accurate clinical end point in translational studies aiming to mitigate ischemia or reperfusion injury by modulating donor quality and recipient factors.

Project description:The data set contains 67 array (lymphochip cDNA array), published in N Engl J Med 2003 Jul 10;349(2):125-38. PMID: 12853585. TITLE: Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. BACKGROUND: The causes and clinical course of acute rejection vary, and it is not possible to predict graft outcome reliably on the basis of available clinical, pathological, and genetic markers. We hypothesized that previously unrecognized molecular heterogeneity might underlie some of the variability in the clinical course of acute renal allograft rejection and in its response to treatment. METHODS: We used DNA microarrays in a systematic study of gene-expression patterns in biopsy samples from normal and dysfunctional renal allografts. A combination of exploratory and supervised bioinformatic methods was used to analyze these profiles. : We found consistent differences among the gene-expression patterns associated with acute rejection, nephrotoxic effects of drugs, chronic allograft nephropathy, and normal kidneys. The gene-expression patterns associated with acute rejection suggested at least three possible distinct subtypes of acute rejection that, although indistinguishable by light microscopy, were marked by differences in immune activation and cellular proliferation. Since the gene-expression patterns pointed to substantial variation in the composition of immune infiltrates, we used immunohistochemical staining to define these subtypes further. This analysis revealed a striking association between dense CD20+ B-cell infiltrates and both clinical glucocorticoid resistance (P=0.01) and graft loss (P<0.001). CONCLUSIONS: Systematic analysis of gene-expression patterns provides a window on the biology and pathogenesis of renal allograft rejection. Biopsy samples from patients with acute rejection that are indistinguishable on conventional histologic analysis reveal extensive differences in gene expression, which are associated with differences in immunologic and cellular features and clinical course. The presence of dense clusters of B cells in a biopsy sample was strongly associated with severe graft rejection, suggesting a pivotal role of infiltrating B cells in acute rejection. A disease state experiment design type is where the state of some disease such as infection, pathology, syndrome, etc is studied. Disease State: normal vs disease Keywords: disease_state_design Using regression correlation

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A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276.

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A risk assessment model of acute liver allograft rejection by genetic polymorphism of CD276.

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