Interpreting Macrophage Transcripts In Human T Cell-Mediated Rejection

  • Author / Creator
    Badr, Dina EFA
  • The two types of rejection identified in the Banff histopathologic diagnosis are T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). TCMR is most common early post-transplant while ABMR is the main cause of late graft loss. Kidney transplant TCMR is diagnosed histologically by interstitial inflammation and tubulitis, dominated by T cells and cells of the monocyte-macrophage-dendritic cell (MMDC) lineage. TCMR is mediated by cognate T cell recognition of donor antigen in the allograft. We hypothesized that the transcripts preferentially increased in kidney allografts with TCMR compared to ABMR will reflect MMDC interaction with activated effector T cells. We used gene expression analysis to define the top transcripts preferentially increased in TCMR versus ABMR in 703 clinically-indicated human kidney transplant biopsies. Transcripts for the metalloprotease ADAMDEC1 and chemokines CXCL13 and CCL18 were the top three preferentially increased in TCMR versus ABMR, their expression was also higher when compared to non specific acute kidney injury and non TCMR biopsies, and correlated with the histologic lesions diagnostic for TCMR and with the inflammatory burden in biopsies.. Further analyses identified the chemokine CCL19 as the most strongly increased in TCMR after CXCL13 and CCL18. CCL19 transcript showed similar associations as CXCL13 and CCL18 but to a lesser degree. In vitro studies identified heterogeneous effects on ADAMDEC1, CXCL13, and CCL18 expression in response to macrophage differentiation, and activation following interaction with activated effector T cells but not IFNG alone. Our study suggests that ADAMDEC1, CXCL13, CCL18 are macrophage transcripts capable of differentiating TCMR from ABMR and reflect monocyte to macrophage differentiation, and macrophage interaction with effector T cells

  • Subjects / Keywords
  • Graduation date
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
    • Department of Medicine
  • Specialization
    • Experimental Medicine
  • Supervisor / co-supervisor and their department(s)
    • Halloran, Philip (Medicine)
  • Examining committee members and their departments
    • Sis, Banu (Laboratory Medicine and Pathology)
    • Kaplan, Bruce (Mayo Clinic)
    • Halloran, Philip (Medicine)
    • Hanington, Patrick (Public Health)
    • Vliagoftis, Harissios (Medicine)