Browsing by Subject "Graft rejection"

Now showing 1 - 4 of 4
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    Combined Analysis of GAD65, miR-375, and Unmethylated Insulin DNA Following Islet Transplantation in Patients With T1D
    (Endocrine Society, 2019-02) Roels, Sarah; Costa, Olivier R.; Tersey, Sarah A.; Stangé, Geert; De Smet, Dieter; Balti, Eric V.; Gillard, Pieter; Keymeulen, Bart; Ling, Zhidong; Pipeleers, Daniel G.; Gorus, Frans K.; Mirmira, Raghavendra G.; Martens, Geert A.; Pediatrics, School of Medicine
    Aim: Several biomarkers have been proposed to detect pancreatic β cell destruction in vivo but so far have not been compared for sensitivity and significance. Methods: We used islet transplantation as a model to compare plasma concentrations of miR-375, 65-kDa subunit of glutamate decarboxylase (GAD65), and unmethylated insulin DNA, measured at subpicomolar sensitivity, and study their discharge kinetics, power for outcome prediction, and detection of graft loss during follow-up. Results: At 60 minutes after transplantation, GAD65 and miR-375 consistently showed near-equimolar and correlated increases proportional to the number of implanted β cells. GAD65 and miR-375 showed comparable power to predict poor graft outcome at 2 months, with areas under the curve of 0.833 and 0.771, respectively (P = 0.53). Using receiver operating characteristic analysis, we defined likelihood ratios (LRs) for rationally selected result intervals. In GADA-negative recipients (n = 28), GAD65 <4.5 pmol/L (LR = 0.15) and >12.2 pmol/L (LR = ∞) predicted good and poor outcomes, respectively. miR-375 could be used in all recipients irrespective of GAD65 autoantibody status (n = 46), with levels <1.4 pmol/L (LR = 0.14) or >7.6 pmol/L (LR = 9.53) as dual thresholds. The posttransplant surge of unmethylated insulin DNA was inconsistent and unrelated to outcome. Combined measurement of these three biomarkers was also tested as liquid biopsy for β cell death during 2-month follow-up; incidental surges of GAD65, miR-375, and (un)methylated insulin DNA, alone or combined, were confidently detected but could not be related to outcome. Conclusions: GAD65 and miR-375 performed equally well in quantifying early graft destruction and predicting graft outcome, outperforming unmethylated insulin DNA.
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    Impact of Variant Donor Hepatic Arterial Anatomy on Clinical Graft Outcomes in Liver Transplantation
    (Wiley, 2018-10) Schroering, Joel R.; Kubal, Chandrashekhar A.; Fridell, Jonathan A.; Hathaway, Taylor J.; Robinson, Ross C.; Mangus, Richard S.; Surgery, School of Medicine
    Standard hepatic arterial anatomy is composed of the common hepatic artery proceeding from the celiac trunk and giving rise to the gastroduodenal artery (GDA) and proper hepatic arteries. Reconstruction of the hepatic arterial supply during liver transplantation, often complex in nature, can be required in cases of accessory or replaced vessels. A recent review summarized the hepatic arterial anatomy reported in over 19,000 cases from 20 individual studies. (1) It has been suggested that the presence of nonstandard donor arterial anatomy may be related to an increased incidence of hepatic artery thrombosis (HAT).(2) Although the overall incidence of HAT is low, it can have devastating effects, including the need for retransplantation, long-term biliary complications, and increased patient mortality. This article describes the arterial anatomy in a large number of liver transplants, with routine anastomosis of a very short hepatic artery and routine reconstruction of the accessory right hepatic artery to the GDA. Study outcomes include incidence of HAT within 30 days of transplant, early graft loss up to 1 year after transplant, and 10-year graft survival.
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    Metabolomic Characterization of Human Model of Liver Rejection Identifies Aberrancies Linked to Cyclooxygenase (COX) and Nitric Oxide Synthase (NOS)
    (International Scientific Information, 2019-06-11) Skill, Nicholas J.; Elliott, Campbell M.; Ceballos, Brian; Saxena, Romil; Pepin, Robert; Bettcher, Lisa; Ellensberg, Matthew; Raftery, Daniel; Maluccio, Mary A.; Ekser, Burcin; Mangus, Richard S.; Kubal, Chandrashekhar A.; Surgery, IU School of Medicine
    BACKGROUND Acute liver rejection (ALR), a significant complication of liver transplantation, burdens patients, healthcare payers, and the healthcare providers due to an increase in morbidity, cost, and resources. Despite clinical resolution, ALR is associated with an increased risk of graft loss. A unique protocol of delayed immunosuppression used in our institute provided a model to characterize metabolomic profiles in human ALR. MATERIAL AND METHODS Twenty liver allograft biopsies obtained 48 hours after liver transplantation in the absence of immunosuppression were studied. Hepatic metabolites were quantitated in these biopsies by liquid chromatography and mass spectroscopy (LC/MS). Metabolite profiles were compared among: 1) biopsies with reperfusion injury but no histological evidence of rejection (n=7), 2) biopsies with histological evidence of moderate or severe rejection (n=5), and 3) biopsies with histological evidence of mild rejection (n=8). RESULTS There were 133 metabolites consistently detected by LC/MS and these were prioritized using variable importance to projection (VIP) analysis, comparing moderate or severe rejection vs. no rejection or mild rejection using partial least squares discriminant statistical analysis (PLS-DA). Twenty metabolites were identified as progressively different. Further PLS-DA using these metabolites identified 3 metabolites (linoleic acid, γ-linolenic acid, and citrulline) which are associated with either cyclooxygenase or nitric oxide synthase functionality. CONCLUSIONS Hepatic metabolic aberrancies associated with cyclooxygenase and nitric oxide synthase function occur contemporaneous with ALR. Additional studies are required to better characterize the role of these metabolic pathways to enhance utility of the metabolomics approach in diagnosis and outcomes of ALR.
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    Treatment with placenta-derived mesenchymal stem cells mitigates development of bronchiolitis obliterans in a murine model
    (Elsevier, 2014) Zhao, Yunge; Gillen, Jacob R.; Harris, David A.; Kron, Irving L.; Murphy, Michael P.; Lau, Christine L.; Surgery, School of Medicine
    Objective: Bone marrow-derived mesenchymal stem cells (MSCs) have shown therapeutic potential in acute lung injury. Recently, placenta-derived human mesenchymal stem cells (PMSCs) have shown similarities with bone marrow-derived MSCs in terms of regenerative capabilities and immunogenicity. This study investigates the hypothesis that treatment with PMSCs reduces the development of bronchiolitis obliterans in a murine heterotopic tracheal transplant model. Methods: A murine heterotopic tracheal transplant model was used to study the continuum from acute to chronic rejection. In the treatment groups, PMSCs or PMSC-conditioned medium (PMSCCM) were injected either locally or intratracheally into the allograft. Phosphate-buffered saline (PBS) or blank medium was injected in the control groups. Tracheal luminal obliteration was assessed on sections stained with hematoxylin and eosin. Infiltration of inflammatory and immune cells and epithelial progenitor cells was assessed using immunohistochemistry and densitometric analysis. Results: Compared with injection of PBS, local injection of PMSCs significantly reduced luminal obliteration at 28 days after transplantation (P = .015). Intratracheal injection of PMSCs showed similar results to local injection of PMSCs compared with injection of PBS and blank medium (P = .022). Tracheas treated with PMSC/PMSCCM showed protection against the loss of epithelium on day 14, with an increase in P63+CK14+ epithelial progenitor cells and Foxp3+ regulatory T cells. In addition, injection of PMSCs and PMSCCM significantly reduced the number of neutrophils and CD3+ T cells on day 14. Conclusions: This study demonstrates that treatment with PMSCs is protective against the development of bronchiolitis obliterans in an heterotopic tracheal transplant model. These results indicate that PMSCs could provide a novel therapeutic option to reduce chronic rejection after lung transplant.