title: Tubulitis after renal transplantation: demonstration of an association between CD103+ T cells, transforming growth factor beta1 expression and rejection grade.
abstract: BACKGROUND
  Tubulitis is a defining feature for the diagnosis and management of acute renal allograft rejection. Lymphocytes extracted from rejecting renal tissue are known to express the alphaEbeta7-integrin (CD103), a receptor for E-cadherin expressed on epithelial cells. In this study, expression of CD103 was examined in situ in tubulitis associated with acute rejection.
  
  
  METHODS
  Immuno-labeling detected CD8+ and CD103+ lymphocytes and E-cadherin on epithelial cells in cryostat sections from 34 diagnostic biopsy specimens and a limited number of transplant nephrectomies. CD8+ and CD103+ intratubular cells were enumerated as mean numbers per tubular crosssection and median values were compared between rejection grades as were median ratios of CD103+ to CD8+ cells. Active transforming growth factor (TGF) beta1 was quantified in paraffin sections by immunofluorescence and confocal microscopical analysis. A parallel in vitro study quantified CD103+ T cells after allospecific activation with and without exogenous TGFbeta1.
  
  
  RESULTS
  CD8+ T cells were present in tubules and tubular interstitium in acute rejection. CD103+ T cells were restricted exclusively to the tubules. The numbers of intratubular CD8+ and CD103+ cells and the ratio of intratubular CD103+ to CD8+ cells increased significantly with tubulitis score (P values 0.005, 0.009, and 0.02, respectively). TGFbeta1 expression was wide-spread in tubules also increasing significantly with tubulitis score (P=0.034). In chronic rejection, CD103+ T cells and TGFbeta1 were present within both tubules and interstitial cell populations. The in vitro study demonstrated that addition of TGFbeta1 to activated, alloantigen-specific T cells increased the proportion of CD8+ cells that also expressed CD103.
  
  
  CONCLUSIONS
  These data indicate that specific upregulation of the alphaEbeta7-integrin by activated, intratubular T cells in acute renal allograft rejection could be a consequence of exposure to high local concentrations of TGFbeta1. The capacity of CD103+ T cells to bind E-cadherin on tubular epithelial cells may be an important factor in the pathogenesis of specific tissue damage observed in acute renal allograft rejection.
authors.affiliation: Department of Surgery, Medical School, University of Newcastle, Newcastle upon Tyne, UK.
authors.forename: H
authors.initials: H
authors.lastname: Robertson
authors.forename: W K
authors.initials: WK
authors.lastname: Wong
authors.forename: D
authors.initials: D
authors.lastname: Talbot
authors.forename: A D
authors.initials: AD
authors.lastname: Burt
authors.forename: J A
authors.initials: JA
authors.lastname: Kirby
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D001706:Biopsy; D015820:Cadherins / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology*; D009393:Nephritis / Q000209:etiology; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D053773:Transforming Growth Factor beta1
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D039001:Integrin alpha Chains; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C091367:alpha E integrins