Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction

Masaaki Sato, Shin Hirayama, Yasushi Matsuda, Dirk Wagnetz, David M. Hwang, Zehong Guan, Mingyao Liu, Shaf Keshavjee

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26 Citations (Scopus)

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). Conclusion. 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.

Original languageEnglish
Pages (from-to)1398-1405
Number of pages8
JournalTransplantation
Volume91
Issue number12
DOIs
Publication statusPublished - 2011 Jun 27
Externally publishedYes

Keywords

  • Bronchiolitis obliterans syndrome
  • Chronic inflammation
  • Chronic rejection
  • Lung transplantation
  • Lymphoid neogenesis

ASJC Scopus subject areas

  • Transplantation

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  • Cite this

    Sato, M., Hirayama, S., Matsuda, Y., Wagnetz, D., Hwang, D. M., Guan, Z., Liu, M., & Keshavjee, S. (2011). Stromal activation and formation of lymphoid-like stroma in chronic lung allograft dysfunction. Transplantation, 91(12), 1398-1405. https://doi.org/10.1097/TP.0b013e31821b2f7a