title: Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction.
abstract: BACKGROUND
  Lymphoid neogenesis is associated with the development of chronic lung allograft dysfunction (CLAD). Activation of stromal resident cells may be an important mechanism of lymphoid neogenesis.
  
  
  METHODS
  Twenty CLAD lungs explanted for retransplantation were immunohistochemically examined for lymphoid neogenesis, ectopic lymphoid chemokines, and dendritic cells (DCs). Formation of peripheral lymph node addressin (PNAd)+ high endothelial venule (HEV)-like vessels was examined in 134 transbronchial biopsies taken over 2 years posttransplant from 20 consecutive lung transplant recipients.
  
  
  RESULTS
  CLAD lungs were characterized by higher grades of CXCL12 in alveolar (P=0.002) and airway epithelial cells (P=0.001), CCL21+ lymph vessels (P=0.01), and infiltration of DC-specific intercellular adhesion molecule-grabbing nonintegrin+ immature DCs (P=0.056) than normal control lungs. Activation of stromal resident cells in CLAD lungs was highlighted by formation of lymphoid-like stroma including expression of CCL21 and CXCL13, fibroblastic reticular-like cells and DC-specific lysosome-associated membrane protein+ mature DCs in association with a significantly larger number of lymphoid aggregates (P<0.001) with lymphangitc distribution compared with normal lungs. A larger number of PNAd+ HEV-like vessels were also observed outside of lymphoid aggregates with a lymphangitic distribution (P<0.001). HEV-like vessels in transbronchial biopsies were more graded in lungs that eventually developed CLAD (n=7) than those that did not (n=13) by 3 years after transplantation (P=0.001).
  
  
  CONCLUSIONS
  Lymphoid neogenesis associated with CLAD accompanies activation of stromal resident cells and formation of lymphoid-like stroma. Induction of PNAd+ HEV-like vessels occurs before the manifestation of CLAD.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Institute of Medical Science, Toronto, ON, Canada.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.forename: Shin
authors.initials: S
authors.lastname: Hirayama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Matsuda
authors.forename: Dirk
authors.initials: D
authors.lastname: Wagnetz
authors.forename: David M
authors.initials: DM
authors.lastname: Hwang
authors.forename: Zehong
authors.initials: Z
authors.lastname: Guan
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000954:Antigens, Surface / Q000096:biosynthesis; D001706:Biopsy; D054421:Chemokine CCL21 / Q000096:biosynthesis; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D054382:Chemokine CXCL13 / Q000096:biosynthesis; D003713:Dendritic Cells; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016040:Lung Transplantation / Q000009:adverse effects*; D008198:Lymph Nodes / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology*; D008565:Membrane Proteins / Q000096:biosynthesis; D017154:Stromal Cells / Q000166:cytology; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D000954:Antigens, Surface; C515478:CCL21 protein, human; C515255:CXCL12 protein, human; C110663:CXCL13 protein, human; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D054382:Chemokine CXCL13; C069886:L-selectin counter-receptors; D008565:Membrane Proteins