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The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation¹

Masaaki Sato^*, Shin Hirayama^*, David M. Hwang^*,, Humberto Lara-Guerra^*, Dirk Wagnetz^*, Thomas K. Waddell^*, Mingyao Liu^* and Shaf Keshavjee^2,*

^* Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute and Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada

Chronic rejection after lung transplantation is manifested as obliterative bronchiolitis (OB). The development of de novo lymphoid tissue (lymphoid neogenesis) may contribute to local immune responses in small airways. Compared with normal lungs, the lung tissue of 13 lung transplant recipients who developed OB demonstrated a significantly larger number of small, airway-associated, peripheral node addressin-positive (PNAd⁺) high endothelial venules (HEVs) unique to lymphoid tissue (p < 0.001). HEVs were most abundant in lesions of lymphocytic bronchiolitis and "active" OB infiltrated by lymphocytes compared with those of "inactive" OB. T cells in lymphocytic bronchiolitis and active OB were predominantly of the CD45RO⁺CCR7^– effector memory phenotype. Similar lymphoid tissue was also observed in the rat lung after intrapulmonary transplantation of allograft trachea (Brown Norway (BN) to Lewis), but not after isograft transplantation. Subsequent orthotopic transplantation of the recipient Lewis lung containing a BN trachea into an F₁ (Lewis x BN) rat demonstrated stable homing of Lewis-derived T cells in the lung and their Ag-specific effector function against the secondary intrapulmonary BN trachea. In conclusion, we found de novo lymphoid tissue in the lung composed of effector memory T cells and HEVs but lacking delineated T cell and B cell zones. This de novo lymphoid tissue may play a critical role in chronic local immune responses after lung transplantation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Canadian Cystic Fibrosis Foundation. M.S. is a recipient of Wyeth/Canadian Institutes of Health Research Rx&D Industrial Partner Program Fellowship (2005–2007) and Canadian Cystic Fibrosis Foundation Postdoctoral Fellowship (2007–2009).

² Address correspondence and reprint requests to Dr. Shaf Keshavjee, Toronto Lung Transplant Program, Toronto General Hospital, 200 Elizabeth Street 9N947, Toronto, Ontario, Canada M5G 2C4. E-mail address: shaf.keshavjee{at}uhn.on.ca

³ Abbreviations used in this paper: TLO, tertiary lymphoid organ; BALT, bronchus-associated lymphoid tissue; BN, Brown Norway; BOS, bronchiolitis obliterans; ELT, effector lymphoid tissue; HEV, high endothelial venule; iBALT, inducible BALT; MAdCAM, mucosal addressin cell adhesion molecule; OB, obliterative bronchiolitis; PNAd, peripheral node addressin.