Marlon F Levy

Baylor University, Waco, Texas, United States

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Publications (149)550.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and sensitive detection of islet graft damage is essential for improving posttransplant outcomes. MicroRNA 375 (miR375) has been reported as a biomarker of pancreatic β-cell death in small animal models. The miR375 levels were measured in purified human islets, sera from patients with autologous and allogeneic islet transplantation as well as total pancreatectomy alone (nontransplanted group). The miR375 levels were also determined in a miniaturized in vitro tube model comprising human islets and autologous blood. The miR375 expression level in islets was dose-dependent (P < 0.001) and significantly elevated after islet damage in plasma in the in vitro model (P = 0.003). Clinical analysis revealed that circulating miR375 levels in both autologous and allogeneic islet recipients were significantly elevated for 7 days after islet infusion, compared with the nontransplanted group (P = 0.005 and <0.001, respectively). Furthermore, miR375 detected the difference in islet graft damage among 3 different anti-inflammatory protocols for clinical autologous transplantation (P < 0.01). Circulating miR375 can be a reliable biomarker to detect graft damage in clinical islet transplantation because serum C-peptide and proinsulin levels are difficult to interpret due to the influence of multiple factors, such as β-cell stress and physiological response.
    Transplantation 03/2015; DOI:10.1097/TP.0000000000000625 · 3.78 Impact Factor
  • Molecular Endocrinology 12/2014; · 4.20 Impact Factor
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    ABSTRACT: Nuclear factor of activated T cells (NFAT) is activated by calcineurin in response to calcium signals derived by metabolic and inflammatory stress to regulate genes in pancreatic islets. Here we show that NFAT targets MAPKs, p300, and histone deacetylases (HDACs) to gene promoters to differentially regulate insulin and TNF-α genes. NFAT and ERK associated with the insulin gene promoter in response to GLP-1, while NFAT formed complexes with p38 and JNK upon promoters of the TNF-α gene in response to IL-1β. Translocation of NFAT and MAPKs to gene promoters was calcineurin/NFAT-dependent, and complex stability required MAPK activity. Knocking down NFATc2 expression, eliminating NFAT DNA binding sites, or interfering with NFAT nuclear import prevented association of MAPKs with gene promoters. Inhibiting p38 and JNK activity increased NFAT-ERK association with promoters, which repressed TNF-α and enhanced insulin gene expression. Moreover, inhibiting p38 and JNK induced a switch from NFAT-p38/JNK-p300 to NFAT-ERK-HDAC3 complex formation upon the TNF-α promoter, which resulted in gene repression. HAT/HDAC exchange was reversed on the insulin gene by p38/JNK inhibition in the presence of GLP-1, which enhanced gene expression. Overall, these data indicate that NFAT directs signaling enzymes to gene promoters in islets, which contribute to protein-DNA complex stability and promoter regulation. Furthermore, the data suggest that TNF-α can be repressed and insulin production can be enhanced by selectively targeting signaling components of NFAT-MAPK transcriptional/signaling complex formation in pancreatic β cells. These findings have therapeutic potential for suppressing islet inflammation while preserving islet function in diabetes and islet transplantation.
    Molecular Endocrinology 12/2014; 29(2):me20141066. DOI:10.1210/me.2014-1066 · 4.20 Impact Factor
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    ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication associated with the transplant recipient. We chronicle a case of PTLD in a failed graft presenting as a small bowel obstruction in a pancreas-only transplant patient. While typical symptoms may be elusive in the complex immunosuppressed patient, graft pain along with persistent graft pancreatitis and a positive Epstein-Barr viremia should raise suspicion for an underlying PTLD.
    Proceedings (Baylor University. Medical Center) 10/2014; 27(4):346-348.
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    ABSTRACT: Objectives Adequate hepatic arterial (HA) flow to the bile duct is essential in liver transplantation. This study was conducted to determine if the ratio of directly measured HA flow to weight is related to the occurrence of biliary complications after deceased donor liver transplantation.MethodsA retrospective review of 2684 liver transplants carried out over a 25-year period was performed using data sourced from a prospectively maintained database. Rates of biliary complications (biliary leaks, anastomotic and non-anastomotic strictures) were compared between two groups of patients with HA flow by body weight of, respectively, <5 ml/min/kg (n = 884) and ≥5 ml/min/kg (n = 1800).ResultsPatients with a lower ratio of HA flow to weight had higher body weight (92 kg versus 76 kg; P < 0.001) and lower HA flow (350 ml/min versus 550 ml/min; P < 0.001). A lower ratio of HA flow to weight was associated with higher rates of biliary complications at 2 months, 6 months and 12 months (19.8%, 28.2% and 31.9% versus 14.8%, 22.4% and 25.8%, respectively; P < 0.001).ConclusionsA ratio of HA flow to weight of < 5 ml/min/kg is associated with higher rates of biliary complications. This ratio may be a useful parameter for application in the prevention and early detection of biliary complications.
    HPB 08/2014; DOI:10.1111/hpb.12318 · 2.05 Impact Factor
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    ABSTRACT: Pancreas preservation is a major factor influencing the results of islet cell transplantation. This study evaluated the effects of 2 different solutions for pancreatic ductal perfusion (PDP) at organ procurement.
    Pancreas 07/2014; DOI:10.1097/MPA.0000000000000196 · 3.01 Impact Factor
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    ABSTRACT: The generation of insulin-secreting cells from nonendocrine pancreatic epithelial cells (NEPEC) has been demonstrated for potential clinical use in the treatment of diabetes. However, previous methods either had limited efficacy or required viral vectors, which hinder clinical application. In this study, we aimed to establish an efficient method of insulin-secreting cell generation from NEPEC without viral vectors. We used nonislet fractions from both research-grade human pancreata from brain-dead donors and clinical pancreata after total pancreatectomy with autologous islet transplantation to treat chronic pancreatitis. It is of note that a few islets could be mingled in the nonislet fractions, but their influence could be limited. The NeuroD1 gene was induced into NEPEC using an effective triple lipofection method without viral vectors to generate insulin-secreting cells. The differentiation was promoted by adding a growth factor cocktail into the culture medium. Using the research-grade human pancreata, the effective method showed high efficacy in the differentiation of NEPEC into insulin-positive cells that secreted insulin in response to a glucose challenge and improved diabetes after being transplanted into diabetic athymic mice. Using the clinical pancreata, similar efficacy was obtained, even though those pancreata suffered chronic pancreatitis. In conclusion, our effective differentiation protocol with triple lipofection method enabled us to achieve very efficient insulin-secreting cell generation from human NEPEC without viral vectors. This method offers the potential for supplemental insulin-secreting cell transplantation for both allogeneic and autologous islet transplantation.
    Human Gene Therapy Methods 05/2014; DOI:10.1089/hgtb.2013.122 · 1.64 Impact Factor
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    ABSTRACT: The instant blood-mediated inflammatory response (IBMIR) has been shown as a major factor that causes damage to transplanted islets. Withaferin A (WA), an inhibitor of nuclear factor (NF) κB, was shown to suppress the inflammatory response in islets and improve syngeneic islet graft survival in mice. We investigated how treating islets with NF-κB inhibitors affected IBMIR using an in vitro human autologous blood islet model. Human islets were pretreated with or without NF-κB inhibitors WA or CAY10512 before mixing autologous blood in a miniaturized in vitro tube model. Plasma samples were collected at multiple time points and used for the measurement of C-peptide, proinsulin, thrombin-antithrombin (TAT) complex, and a panel of proinflammatory cytokines. Infiltration of neutrophils into islets was analyzed using immunohistochemistry. Rapid release of C-peptide and proinsulin was observed 3 hr after mixing islets and blood in the control group, but not in the NF-κB inhibitor-treated groups, whereas TAT levels were elevated in all three groups with a peak at 6 hr. Significant elevation of proinflammatory cytokines was observed in the control group after 3 hr, but not in the treatment groups. Significant inhibition of neutrophil infiltration was also observed in the WA group compared with the control (P<0.001) and CAY10512 (P<0.001) groups. A miniaturized in vitro tube model can be useful in investigating IBMIR. The presence of NF-κB inhibitor could alleviate IBMIR, thus improving the survival of transplanted islets. Protection of islets in the peritransplant phase may improve long-term graft outcomes.
    Transplantation 05/2014; 98(5). DOI:10.1097/TP.0000000000000107 · 3.78 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-801-S-802. DOI:10.1016/S0016-5085(14)62898-5 · 13.93 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB374. DOI:10.1016/j.gie.2014.02.449 · 4.90 Impact Factor
  • Gastrointestinal Endoscopy 05/2014; 79(5):AB373-AB374. DOI:10.1016/j.gie.2014.02.448 · 4.90 Impact Factor
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    ABSTRACT: Islet cell transplantation is a promising beta cell replacement therapy for patients with brittle type 1 diabetes as well as refractory chronic pancreatitis. Despite the vast advancements made in this field, challenges still remain in achieving high frequency and long-term successful transplant outcomes. Here we review recent advances in understanding the role of inflammation in islet transplantation and development of strategies to prevent damage to islets from inflammation. The inflammatory response associated with islets has been recognized as the primary cause of early damage to islets and graft loss after transplantation. Details on cell signaling pathways in islets triggered by cytokines and harmful inflammatory events during pancreas procurement, pancreas preservation, islet isolation, and islet infusion are presented. Robust control of pre- and peritransplant islet inflammation could improve posttransplant islet survival and in turn enhance the benefits of islet cell transplantation for patients who are insulin dependent. We discuss several potent anti-inflammatory strategies that show promise for improving islet engraftment. Further understanding of molecular mechanisms involved in the inflammatory response will provide the basis for developing potent therapeutic strategies for enhancing the quality and success of islet transplantation.
    International Journal of Endocrinology 04/2014; 2014:451035. DOI:10.1155/2014/451035 · 1.52 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: Islet transplantation is a new treatment for achieving insulin independence for severe diabetic patients. However, major drawbacks of this treatment are the long graft survival, the necessity for immunosuppressive drugs and the efficacy of transplantation. Donor specific transfusion (DST) has been shown to reduce rejection after organ transplantation, potentially through enhanced regulatory T cell (Treg) activity. However, recent findings have shown that activated Treg can be converted into Th17 cells. We focused on histone deacetylase inhibitors (HDACi) since it was reported that inhibition of HDAC activity prevented Treg differentiation into IL17-producing cells. We therefore sought to enhance Treg while suppressing Th17 cells using DST with HDACi to prolong graft survival. To stimulate Treg by DST, we used donor splenocytes. In DST with HDACi group, Foxp3 mRNA expression and Treg population increased in the thymus and spleen, whereas Th17 population decreased. qPCR analysis of lymphocyte mRNA indicated that Foxp3, IL-10, and TGF-b expression increased. However, interleukin 17a, Stat3 (Th17) and IFN-g expression decreased in DST + HDACi group, relative to DST alone. Moreover, DST treated with HDACi prolonged graft survival relative to controls in mice islet transplantation. DST with HDACi may therefore have utility in islet transplantation. This article is protected by copyright. All rights reserved.
    Transplant International 01/2014; 27(4). DOI:10.1111/tri.12265 · 3.16 Impact Factor
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    ABSTRACT: The aim of this study is to show the effect of donor-specific transfusion (DST) in inducing immunological tolerance mediated by regulatory T cells (Treg) and indoleamine 2,3-dioxygenase (IDO). Skin grafts from H2(d) Balb/c were transplanted into H2(k) C3H/He 7days after the infusion of donor splenocytes, isolated each immune cell populations. Graft survival prolonged in recipients who received splenocytes, MHC class II(+) CD90(-) cells and CD3(-)CD19(-) cells (p<0.001, p<0.05 and p<0.01, respectively). CD11b(+) cell infusion resulted in prolongation of graft survival when compared to CD11c(+) cell infusion (p<0.01). Foxp3(+)CD4(+)CD25(+) T cells were increased after the transplant in recipients infused with CD11b(+) cells (p<0.05). The mixed lymphocyte reaction showed donor-specificity (p<0.001). High IDO expression was observed in CD11b(+) cell infusion group. Graft survival with DST using IDO antagonist (1MT) were not prolonged. In conclusion, DST allows induction of donor-specific tolerance which involves Foxp3(+)CD4(+)CD25(+) T cells and IDO expression.
    Cellular Immunology 06/2013; 283(1-2):81-90. DOI:10.1016/j.cellimm.2013.06.004 · 1.87 Impact Factor
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    ABSTRACT: Liver transplantation is the optimal treatment for patients with hepatocellular carcinoma (HCC) and cirrhosis. This study was conducted to determine the impact of pre-transplant locoregional therapy (LRT) on HCC and our institution's experience with expansion to United Network of Organ Sharing Region 4 T3 (R4T3) criteria. Two hundred and twenty-five patients with HCC (176 meeting Milan and 49 meeting R4T3 criteria) underwent liver transplantation from 2002 to 2008. Compared with the Milan criteria, HCCs in R4T3 criteria displayed less favorable biological features such as higher median alpha-fetoprotein level (21.9 vs. 8.5 ng/mL, p = 0.01), larger tumor size, larger tumor number, and higher incidence of microvascular invasion (22% vs. 5%, p = 0.002). As a result, patients meeting Milan criteria had better five-yr survival (79% vs. 69%, p = 0.03) and a trend toward lower HCC recurrence rates (5% vs. 13%, p = 0.05). Pre-transplant LRT did not affect post-transplant outcomes in patients meeting Milan criteria but did result in lower three-yr HCC recurrence (7% vs. 75%, p < 0.001) and better three-yr survival (p = 0.02) in patients meeting R4T3 criteria. Tumor biology and pre-transplant LRT are important factors that determine the post-transplant outcomes in patients with HCC who meet R4T3 criteria.
    Clinical Transplantation 01/2013; DOI:10.1111/ctr.12089 · 1.49 Impact Factor
  • Pancreas 01/2013; 42(1):175-177. DOI:10.1097/MPA.0b013e3182546e37 · 3.01 Impact Factor
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    ABSTRACT: BACKGROUND: Two adverse effects of sirolimus are hypertriglyceridemia and hypercholesterolemia. These elevated levels often lead clinicians to discontinue the sirolimus from concerns of an increased cardiovascular disease (CVD) risk; however, evidence suggests that sirolimus might be cardioprotective. There are no published reports of sirolimus CVD in liver transplantation. METHODS: We reviewed all 1812 liver recipients who underwent transplantation from 1998 to 2010, identifying a cohort using sirolimus as part of the initial immunosuppression (SRL Cohort) and a control group of the remaining patients from this period where SRL was never given (Non-SRL Control). A prospectively maintained database identified all episodes of myocardial infarction (MI), congestive heart failure (CHF), abdominal aortic aneurysm (AAA), and cerebrovascular accident and tracked triglyceride, high-density and low-density lipoproteins, and total cholesterol levels. A Framingham Risk Model calculated the predicted 10-year risk of CVD for both groups. RESULTS: The SRL Cohort (n=406) is older, more predominantly male, with more pretransplantation hypertension and diabetes and posttransplantation hypertension compared to Non-SRL Controls (n=1005). The SRL Cohort has significantly higher triglyceride, low-density lipoprotein, and cholesterol levels at 6 months and 1 year. There is no difference in MI incidence in the SRL Cohort (1.0% vs. 1.2%) and no difference in AAA, cerebrovascular accident, and CHF. The Framingham Risk Model predicts that the SRL Cohort should have almost double the 10-year risk of CVD compared to the Non-SRL Control (11% vs. 6%). CONCLUSIONS: Sirolimus causes hypertriglyceridemia and hypercholesterolemia, but it does not increase the incidence of MI or other CVDs. Considering the SRL Cohort has more cardiac risk factors and nearly double 10-year predicted CVD risk, the fact that the CVD incidence is similar suggests that sirolimus is in fact cardioprotective.
    Transplantation 12/2012; 95(1). DOI:10.1097/TP.0b013e318279090c · 3.78 Impact Factor
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    ABSTRACT: A major problem after clinical autologous islet transplantation (AIT) is the difficulty in achieving insulin independence. To follow up on our demonstration in a murine model that high-mobility group box 1 (HMGB1) was released from islets and involved in early loss of transplanted islets, we tested the role of HMGB1 in clinical AIT. Serum HMGB1 levels from 15 AIT patients were significantly elevated during islet infusion (7.6 ± 1.2 ng/mL) and 24 hours after infusion (8.0 ± 1.4 ng/mL) compared to admission levels (2.4 ± 0.6 ng/mL). The first elevation of HMGB1 was associated with islet damage, but the later elevation was not. The change in the HMGB1 level from admission to first peak (ΔHMGB1) was significantly higher in the AIT group (8.1 ± 1.1 ng/mL) than in the pancreatectomy-only control (2.2 ± 0.5 ng/mL) (p<0.05). Circulating serum levels of soluble receptor for advanced glycation end products (sRAGE) were also elevated during islet infusion. In vitro studies demonstrated damaged human islets released HMGB1 but not sRAGE. In terms of outcomes, the insulin free group showed significantly lower ΔHMGB1 (5.2 ± 0.6 ng/mL) and higher ΔsRAGE (2.3 ± 0.6 ng/mL) than the insulin-dependent group (10.6 ± 1.9 ng/mL and 0.7 ± 0.2 ng/mL. respectively). The ΔHMGB1 correlated with the number of white blood cell, IP-10, EGF and Eotaxin. In conclusion, serum HMGB1 was elevated in AIT, and could be associated with inflammatory reactions that deteriorate islet engraftment. Therefore, anti-HMGB1 therapy might be a candidate for further improving the outcomes of clinical AIT.
    Cell Transplantation 12/2012; DOI:10.3727/096368912X658980 · 3.57 Impact Factor
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    ABSTRACT: The purification process is one of the most difficult procedures in pancreatic islet isolation. It was demonstrated that the standard purification method using a COBE 2991 cell processor with Ficoll density gradient solution harmed islets mechanically by high shear force. We reported that purification using large bottles with a lower viscosity gradient solution could improve the efficacy of porcine islet purification. In this study, we examined whether the new bottle purification method could improve the purification of human islets. Nine human pancreata from brain-dead donors were used. After pancreas digestion, the digested tissue was divided into three groups. Each group was purified by continuous density gradient using ET-Kyoto and iodixanol gradient solution with either the standard COBE method (COBE group) or the top loading (top group) or bottom loading (bottom group) bottle purification methods. Islet yield, purity, recovery rate after purification, and in vitro and in vivo viability were compared. Islet yield per pancreas weight (IE/g) and the recovery rate in the top group were significantly higher than in the COBE and bottom groups. Furthermore, the average size of purified islets in the top group was significantly larger than in the COBE group, which indicated that the bottle method could reduce the shear force to the islets. In vivo viability was also significantly higher in the top group compared with the COBE group. In conclusion, the top-loading bottle method could improve the quality and quantity of human islets after purification.
    Islets 11/2012; 4(6). DOI:10.4161/isl.23008 · 1.55 Impact Factor
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    ABSTRACT: Islet transplantation is one of the most promising therapies for Type 1 diabetes (T1D). A major issue in islet transplantation is the loss of graft function at late phase. Several studies suggested the involvement of islet-specific T cells in such islet graft dysfunction. In this study, we investigated the breadth and type of glutamic acid decarboxylase 65 (GAD65)-specific T cells in T1D patients after allogeneic islet transplantation. Peripheral blood mononuclear cells (PBMCs) were obtained from islet-transplanted T1D patients during insulin independent period, and cultured for 7 days with pools of GAD65 overlapping peptides in the presence of IL-2. Cytokine secretion profiles of peptide-reactive T cells were analyzed after a short-term re-stimulation with the same peptides, by a multiplex bead-based cytokine assay and by an intracytoplasmic cytokine detection assay. Robust GAD65-specific CD4⁺ and CD8⁺ T cell responses were detected in patients who eventually developed chronic graft dysfunction. Multiple GAD65 peptides were found to induce specific T cell responses in these patients, indicating that the repertoire of GAD65-specific T cells was broad. Furthermore, GAD65-specific CD4⁺ T cells were composed of heterogeneous populations which differentially expressed cytokines including IFN-γ and Type 2 cytokines, but not IL-10. In contrast, patients who showed only marginal GAD65-specific T cell responses maintained substantially longer graft survival and insulin independence. In conclusion, our study suggests that the emergence of islet-specific T cells precedes the development of chronic graft dysfunction in islet-transplanted patients. Thus, our observations support the hypothesis that these islet-specific T cells contribute to the development of chronic islet graft dysfunction.
    Cell Transplantation 09/2012; DOI:10.3727/096368912X654993 · 3.57 Impact Factor

Publication Stats

3k Citations
550.80 Total Impact Points

Institutions

  • 2001–2013
    • Baylor University
      • Institute of Biomedical Studies
      Waco, Texas, United States
  • 1999–2012
    • Baylor Health Care System
      • • Baylor All Saints Medical Center
      • • Internal Medicine
      Dallas, Texas, United States
  • 2011
    • The University of Tokushima
      Tokusima, Tokushima, Japan
  • 2004–2010
    • Texas Transplant Institute
      San Antonio, Texas, United States
    • Methodist Dallas Medical Center
      Dallas, Texas, United States
  • 2009
    • Okayama University
      Okayama, Okayama, Japan
  • 1998–2006
    • University of Texas Southwestern Medical Center
      • • Department of Pharmacology
      • • Department of Anesthesiology and Pain Management
      Dallas, TX, United States
  • 2003
    • Hackensack University Medical Center
      Хакенсак, New Jersey, United States
  • 2002
    • University of Texas at Dallas
      Richardson, Texas, United States