Liver Antigen - Presenting Cells in Hepatic Injury and Transplantation

Summary

Principal Investigator: Angus W Thomson
Abstract: We propose the overarching hypothesis that liver non-parenchymal, antigen-presenting cells (ARC) serve as key regulators of hepatic-based inflammatory/immune responses. The proposed Program Project will bring together the collective expertise of a highly-experienced and interactive, interdisciplinary group of investigators, established in the study of APC function, hepatic ischemia-reperfusion (I/R) injury, liver immunobiology, and transplantation. Complementary skills and expertise of the team will be melded to elucidate mechanisms and resolve apparent paradoxes underlying the distinctive role of specific liver APC populations in innate immunity and regulation of adaptive immunity. There is strong potential for development of novel therapeutic strategies to improve liver allograft outcome. The Program's goal is to understand, through collaborative interaction, mechanisms underlying the role of specific liver APC, that generally dampen systemic immune responses to gut-derived Ags, in regulation of liver injury and hepatic immunity relevant to transplant outcome. Project 1 will focus on mechanisms by which the hepatocyte-derived transcription factor interferon regulatory factor-1 (IRF-1) and hepatocyte injury overwhelm the natural tendency of the liver to suppress inflammatory/immune responses after liver I/R injury. Aim I: will identify the signaling pathways and role of liver APC (DCs, Kupffer cells and stellate cells) in regulation of hepatic IRF-1 expression;Aim II: will elucidate the mechanisms of hepatic IRF-1-mediated liver injury;Aim III: will determine whether IRF-1 blockade can ameliorate liver transplant I/R injury. Project 2 will focus on mechanisms that regulate liver DC maturation and function and determine their role in the initiation and regulation of T cell function and liver transplant outcome. Aim I: will elucidate the role of inducible regulators of Toll-like receptor (TLR) signaling in endotoxin tolerance in liver DC;Aim II: will ascertain the contribution of specific pro- and anti-inflammatory cytokines, expressed in the steady-state and during I/R injury, to endotoxin tolerance in liver DC. Aim III: will establish the contribution of donor DC, TLR4 and negative regulators of TLR signaling in liver DC to T cell responses following experimental liver transplantation;Aim IV: will determine the maturation status of hepatic DC, including expression of negative regulators of maturation, in relation to human liver transplant outcome. Project 3 will define mechanisms by which hepatic stellate cells participate in I/R injury and regulate the function of DC and T lymphocytes in relation to liver transplant outcome. Aim I: will ascertain the influence of hepatic stellate cells on IRF-1 and liver I/R injury;Aim II: will determine mechanisms underlying the regulation of DC and T lymphocyte function by hepatic stellate cells;Aim III: will ascertain the role of hepatic stellate cells in the regulation of liver allograft outcome. These three Projects will be supported by an Administrative Core (Core A), that will co-ordinate programatic functions, an Imaging and Tissue Pathology Core (Core B). and a small animal Transplantation Surgery Core (Core C).
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance
    O Yoshida
    Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Am J Transplant 14:1791-805. 2014
  2. pmc Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury
    John R Klune
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA
    Am J Physiol Gastrointest Liver Physiol 303:G666-73. 2012
  3. pmc Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver
    MAJA STEFANOVIC-RACIC
    Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Diabetes 61:2330-9. 2012
  4. pmc Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO
    Tina L Sumpter
    Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Immunol 189:3848-58. 2012
  5. ncbi Roles of dendritic cells in murine hepatic warm and liver transplantation-induced cold ischemia/reperfusion injury
    Matthew Zhang
    Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Hepatology 57:1585-96. 2013
  6. pmc Hepatic B cells are readily activated by Toll-like receptor-4 ligation and secrete less interleukin-10 than lymphoid tissue B cells
    H Zhang
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Clin Exp Immunol 173:473-9. 2013
  7. pmc CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia-reperfusion injury in mice
    Osamu Yoshida
    Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Hepatology 58:2163-75. 2013
  8. pmc Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells
    C Macedo
    Department of Surgery, Thomas E Starzl Transplantation Institute, Pittsburgh, PA
    Am J Transplant 13:2322-33. 2013
  9. pmc Regulatory myeloid cells in transplantation
    Brian R Rosborough
    1 Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 2 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 3 Address correspondence to Angus W Thomson, Ph D, D Sc, Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Thomas E Starzl Transplantation Institute, 200 Lothrop Street, Biomedical Science Tower W1540, Pittsburgh, PA 15213
    Transplantation 97:367-79. 2014
  10. pmc IL-33 expands suppressive CD11b+ Gr-1(int) and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival
    Heth R Turnquist
    Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Immunol 187:4598-610. 2011

Scientific Experts

  • Angus Thomson
  • Antonino Castellaneta
  • David A Geller
  • Tina L Sumpter
  • Heth R Turnquist
  • Noriko Murase
  • Brian R Rosborough
  • Shinya Ueki
  • Osamu Yoshida
  • Donna B Stolz
  • Benjamin M Matta
  • Shoko Kimura
  • Matthew Zhang
  • Mark Ross
  • Peiyuan Li
  • Allan Tsung
  • John R Klune
  • Sudha Natarajan
  • Rajeev Dhupar
  • Zongxian Cao
  • O Yoshida
  • H Zhang
  • C Macedo
  • Yoram Vodovotz
  • John Evankovich
  • Anthony J Demetris
  • MAJA STEFANOVIC-RACIC
  • K Isse
  • Chao Huang
  • Donna Beer Stolz
  • Kikumi S Ozaki
  • Lifang Shao
  • Mohamed Ezzelarab
  • Chandrashekhar R Gandhi
  • Ryan T Fischer
  • Jon Cardinal
  • Zhiliang Wang
  • Kumiko Isse
  • Lung Yi Lee
  • George V Mazariegos
  • Adriana Zeevi
  • Noor Mohamed Jameel
  • Alin Girnita
  • B M Matta
  • Dàlia Raïch-Regué
  • S Kimura
  • D A Geller
  • M A Ross
  • S Yokota
  • L Dou
  • D Metes
  • Simon C Robson
  • G Chalasani
  • H R Turnquist
  • R Shapiro
  • D B Stolz
  • A F Zahorchak
  • Edwin K Jackson
  • M Castillo-Rama
  • Ying Chang
  • Qiang Du
  • Michael S Turner
  • A Lesniak
  • Zhong Guo
  • B Roysam
  • Nikolaos Dedousis
  • M I Minervini
  • Penelope A Morel
  • Anil Dangi
  • Giorgio Raimondi
  • A J Demetris
  • Donald K Scott
  • Benjamin S Mantell
  • Atsunori Nakao
  • K Grama
  • Wei Yan
  • Gary Nace
  • ROBERT M O'DOHERTY
  • Ian J Sipula
  • Xiao Yang
  • Kikumi Ozaki
  • Zhenlin Zhao
  • Xin Xiao Zheng
  • Takashi Kaizu
  • Hideyoshi Toyokawa
  • Vignesh Packiam
  • Navdeep Nayyar
  • A Jake Demetris
  • Kathryn J Wood
  • Quan Liu

Detail Information

Publications32

  1. pmc DAP12 deficiency in liver allografts results in enhanced donor DC migration, augmented effector T cell responses and abrogation of transplant tolerance
    O Yoshida
    Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Am J Transplant 14:1791-805. 2014
    ..Thus, DAP12 expression in liver grafts regulates donor mDC migration to host lymphoid tissue, alloreactive T cell responses and transplant tolerance. ..
  2. pmc Interferon regulatory factor-2 is protective against hepatic ischemia-reperfusion injury
    John R Klune
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pennsylvania 15213, USA
    Am J Physiol Gastrointest Liver Physiol 303:G666-73. 2012
    ..In summary, IRF2 overexpression protects against I/R injury by decreasing IRF1-dependent injury and may represent a novel therapeutic strategy...
  3. pmc Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver
    MAJA STEFANOVIC-RACIC
    Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
    Diabetes 61:2330-9. 2012
    ..Together, these data demonstrate that DC are elevated in obesity, promote macrophage infiltration of AT and liver, contribute to the determination of tissue immunophenotype, and play a role in systemic metabolic responses to an HFD...
  4. pmc Hepatic stellate cells undermine the allostimulatory function of liver myeloid dendritic cells via STAT3-dependent induction of IDO
    Tina L Sumpter
    Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Immunol 189:3848-58. 2012
    ..In conclusion, by promoting IDO expression, HSCs may act as potent regulators of liver mDCs and function to maintain hepatic homeostasis and tolerogenicity...
  5. ncbi Roles of dendritic cells in murine hepatic warm and liver transplantation-induced cold ischemia/reperfusion injury
    Matthew Zhang
    Thomas E Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Hepatology 57:1585-96. 2013
    ..When Flt3L KO liver was transplanted into WT mice, ALT levels were significantly higher than in WT to WT LTx, with enhanced hepatic necrosis and neutrophil infiltration, indicating a protective role of liver-resident DC...
  6. pmc Hepatic B cells are readily activated by Toll-like receptor-4 ligation and secrete less interleukin-10 than lymphoid tissue B cells
    H Zhang
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Clin Exp Immunol 173:473-9. 2013
    ..These findings suggest that hepatic B cells have the potential to initiate rather than regulate inflammatory responses. ..
  7. pmc CD39 expression by hepatic myeloid dendritic cells attenuates inflammation in liver transplant ischemia-reperfusion injury in mice
    Osamu Yoshida
    Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Hepatology 58:2163-75. 2013
    ..Moreover, portal venous delivery of WT, but not CD39(-/-) liver mDCs, to donor livers immediately post-transplant exerted a protective effect against graft injury in CD39(-/-) to CD39(-/-) liver transplantation...
  8. pmc Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells
    C Macedo
    Department of Surgery, Thomas E Starzl Transplantation Institute, Pittsburgh, PA
    Am J Transplant 13:2322-33. 2013
    ....
  9. pmc Regulatory myeloid cells in transplantation
    Brian R Rosborough
    1 Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 2 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 3 Address correspondence to Angus W Thomson, Ph D, D Sc, Departments of Surgery and Immunology, University of Pittsburgh School of Medicine, Thomas E Starzl Transplantation Institute, 200 Lothrop Street, Biomedical Science Tower W1540, Pittsburgh, PA 15213
    Transplantation 97:367-79. 2014
    ..Moreover, novel IS agents may be designed to target RMC in situ to promote Ag-specific immune regulation in transplantation and to usher in a new era of immune modulation exploiting cells of myeloid origin. ..
  10. pmc IL-33 expands suppressive CD11b+ Gr-1(int) and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival
    Heth R Turnquist
    Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Immunol 187:4598-610. 2011
    ..Specifically, in addition to supporting Th2 responses, IL-33 facilitates regulatory cells, particularly functional CD4(+) Foxp3(+) Tregs that underlie IL-33-mediated cardiac allograft survival...
  11. pmc Histone deacetylase inhibition facilitates GM-CSF-mediated expansion of myeloid-derived suppressor cells in vitro and in vivo
    Brian R Rosborough
    University of Pittsburgh School of Medicine, Thomas E Starzl Transplantation Institute, 200 Lothrop St, Biomedical Science Tower, W1540, Pittsburgh, PA 15213, USA
    J Leukoc Biol 91:701-9. 2012
    ..These findings establish a clinically applicable approach to augment this rare and potent suppressive immune cell population and support a novel mechanism underlying the anti-inflammatory action of HDACi...
  12. pmc Digital transplantation pathology: combining whole slide imaging, multiplex staining and automated image analysis
    K Isse
    Department of Pathology, Division of Transplantation, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
    Am J Transplant 12:27-37. 2012
    ..Regardless, challenges will be overcome and these technologies will enable transplant pathologists to increase information extraction from tissue specimens and contribute to cross-platform biomarker discovery for improved outcomes...
  13. pmc Interferon-γ induces autophagy with growth inhibition and cell death in human hepatocellular carcinoma (HCC) cells through interferon-regulatory factor-1 (IRF-1)
    Peiyuan Li
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Cancer Lett 314:213-22. 2012
    ..Together, these findings show that IFN-γ induces autophagy through IRF-1 signaling pathway and the induction of autophagy contributes to the growth-inhibitory effect of IFN-γ with cell death in human liver cancer cells...
  14. pmc IL-27 production and STAT3-dependent upregulation of B7-H1 mediate immune regulatory functions of liver plasmacytoid dendritic cells
    Benjamin M Matta
    Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    J Immunol 188:5227-37. 2012
    ..These data suggest that IL-27 signaling in pDCs promotes their immunoregulatory function and that IL-27 produced by pDCs contributes to their capacity to regulate immune responses in vitro and in vivo...
  15. pmc Carbon monoxide induces hypothermia tolerance in Kupffer cells and attenuates liver ischemia/reperfusion injury in rats
    Lung Yi Lee
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
    Liver Transpl 17:1457-66. 2011
    ..In conclusion, the pretreatment of donors with CO ameliorates LT-associated I/R injury with increased hepatic HSP70 expression, particularly in the KC population...
  16. pmc Tolerogenic dendritic cells and their role in transplantation
    Mohamed Ezzelarab
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, 200 Lothrop Street, BST W1540, Pittsburgh, PA 15261, USA
    Semin Immunol 23:252-63. 2011
    ..Evaluation of technical and therapeutic logistic issues is an important next step prior to the application of tolerogenic DC in clinical organ transplantation...
  17. ncbi Liver transplant recipients weaned off immunosuppression lack circulating donor-specific antibodies
    Alin Girnita
    Thomas E Starzl Transplantation Institute and Department of Pathology, University of Pittsburgh School of Medicine and Children s Hospital of Pittsburgh, Pennsylvania, USA
    Hum Immunol 71:274-6. 2010
    ..Thus, most of the liver recipients off immunosuppression lacked donor-specific alloAbs. The occurrence of these alloAbs should now be examined prospectively in a drug weaning trial...
  18. pmc Tolerogenic dendritic cells: all present and correct?
    A W Thomson
    Starzl Transplantation Institute, Department of Surgery and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Am J Transplant 10:214-9. 2010
    ..This minireview surveys recent findings that enhance understanding of the functional biology and therapeutic application of tolDC, with special reference to transplantation...
  19. pmc Critical role of interferon regulatory factor-1 in murine liver transplant ischemia reperfusion injury
    Shinya Ueki
    Department of Surgery, Thomas E Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, PA, USA
    Hepatology 51:1692-701. 2010
    ..However, LTx with chimeric liver grafts showed that grafts lacking hepatocellular IRF-1 had better protection compared with those lacking IRF-1 in NPC. The study identifies a critical role for IRF-1 in liver transplant I/R injury...
  20. pmc Tolerogenic dendritic cells and myeloid-derived suppressor cells: potential for regulation and therapy of liver auto- and alloimmunity
    Sudha Natarajan
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Immunobiology 215:698-703. 2010
    ..Herein, we discuss current understanding of liver autoimmunity post-transplantation, along with current approaches for the development of tolerogenic DC, and the potential use of MDSC for the development of stable, Ag-specific tolerance...
  21. ncbi A critical role for IFN regulatory factor 1 in NKT cell-mediated liver injury induced by alpha-galactosylceramide
    Zongxian Cao
    Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    J Immunol 185:2536-43. 2010
    ..Our findings revealed a novel mechanism of NKT cell-mediated liver injury in mice, which has implications in the development of human liver diseases...
  22. pmc Tolerogenic plasmacytoid DC
    Benjamin M Matta
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Eur J Immunol 40:2667-76. 2010
    ....
  23. ncbi Antigen-presenting cell function in the tolerogenic liver environment
    Angus W Thomson
    Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    Nat Rev Immunol 10:753-66. 2010
    ..Here, we review the central role of liver APCs in the regulation of hepatic immune function and also consider how recent insights may be applied in strategies to target liver tolerance for disease therapy...
  24. ncbi Constitutive release of powerful antioxidant-scavenging activity by hepatic stellate cells: protection of hepatocytes from ischemia/reperfusion injury
    Noor Mohamed Jameel
    Thomas E Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
    Liver Transpl 16:1400-9. 2010
    ..Thus, HSCs protect hepatocytes against oxidative damage through the production of a novel protein, the further purification of which may lead to the isolation of a powerful oxygen radical scavenger with clinical applications...
  25. pmc DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability
    Tina L Sumpter
    Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    J Immunol 186:1970-80. 2011
    ..These findings highlight a regulatory role for DAP12 in hepatic DC maturation, and suggest a mechanism whereby this function may be induced/maintained...
  26. ncbi The STATus of PD-L1 (B7-H1) on tolerogenic APCs
    Tina L Sumpter
    Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Eur J Immunol 41:286-90. 2011
    ..These findings also have implications for understanding the inherent function of DCs in non-lymphoid tissues such as the liver and lung, where they are exposed to PAMPs that are found constitutively in the local microenvironment...
  27. pmc HLA-G level on monocytoid dendritic cells correlates with regulatory T-cell Foxp3 expression in liver transplant tolerance
    Antonino Castellaneta
    Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Transplantation 91:1132-40. 2011
    ..Interaction of HLA-G with its receptor, immunoglobulin-like transcript 4 on dendritic cells (DCs) down-regulates their T-cell stimulatory ability...
  28. pmc Hepatic B7 homolog 1 expression is essential for controlling cold ischemia/reperfusion injury after mouse liver transplantation
    Shinya Ueki
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Hepatology 54:216-28. 2011
    ..Human livers up-regulated B7-H1 expression after LT...
  29. pmc Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8(+) T cells in vitro and in vivo
    Ryan T Fischer
    Thomas E Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15238, USA
    Transpl Immunol 25:20-6. 2011
    ..Adoptive cell therapy with alloAg-pulsed RAPA-DC may offer an effective approach to suppression of alloimmunity, with reduced dependence on systemic immunosuppression...
  30. ncbi Hepatic antigen-presenting cells and regulation of liver transplant outcome
    Angus W Thomson
    Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, 200 Lothrop Street, W1540 BST, Pittsburgh, PA 15261, USA
    Immunol Res 50:221-7. 2011
    ..Our studies are also aimed at elucidating mechanisms by which HSC regulate DC and T-cell function. These investigations may provide new targets for therapeutic intervention in liver inflammation...
  31. ncbi IL-33 broadens its repertoire to affect DC
    Heth R Turnquist
    Department of Surgery, Thomas E Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
    Eur J Immunol 39:3292-5. 2009
    ..This commentary discusses several questions raised by these findings, and provides a basis for further evaluation of IL-33 and ST2L in regulation of APC generation and function in both innate and adaptive immunity...