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Cutting Edge: Acute Lung Allograft Rejection Is Independent of Secondary Lymphoid Organs¹

Andrew E. Gelman^*,, Wenjun Li^*, Steven B. Richardson^*, Bernd H. Zinselmeyer, Jiaming Lai^*, Mikio Okazaki^*, Christopher G. Kornfeld^*, Friederike H. Kreisel, Seiichiro Sugimoto^*, Jeremy R. Tietjens^*, John Dempster, G. Alexander Patterson^*, Alexander S. Krupnick^*, Mark J. Miller and Daniel Kreisel^2,*,

^* Department of Surgery and Department of Pathology and Immunology, Washington University, St. Louis, MO 63110; and Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland, United Kingdom

It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c⁺ cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.

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 D.K. was supported by National Heart, Lung, and Blood Institute Grant 1K08HL083983 and by the Thoracic Surgery Foundation for Research and Education.

² Address correspondence and reprint requests to Dr. Daniel Kreisel, Assistant Professor of Surgery, Pathology and Immunology, Campus Box 8234, 660 South Euclid Avenue, Washington University, St. Louis, MO 63110-1013. E-mail address: kreiseld{at}wudosis.wustl.edu

³ Abbreviations used in this paper: EYFP, enhanced yellow fluorescent protein; BALT, bronchus-associated lymphoid tissue; FDC, follicular dendritic cell; PNAd, peripheral node addressin.

⁴ The online version of this article contains supplemental material.