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,¶
,,¶,*,
* Department of Medicine,
Center for Immunobiology,
Department of Anesthesia,
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
¶ Department of Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan;
|| Department of Medicine, Veterans’ Affairs Medical Center and University of Tennessee, Memphis, TN 38104;
# Department of Surgery,
** Department of Pathology, University of Wisconsin, Madison School of Medicine and Public Health, Madison, WI 53792; and
Department of Medicine,
* Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Primary graft dysfunction (PGD) is a major complication following lung transplantation. We reported that anti-type V collagen (col(V)) T cell immunity was strongly associated with PGD. However, the role of preformed anti-col(V) Abs and their potential target in PGD are unknown. Col(V) immune serum, purified IgG or B cells from col(V) immune rats were transferred to WKY rat lung isograft recipients followed by assessments of lung pathology, cytokines, and PaO2/FiO2, an index of lung dysfunction in PGD. Immune serum, purified IgG, and B cells all induced pathology consistent with PGD within 4 days posttransfer; up-regulated IFN-
, TNF-
, and IL-1β locally; and induced significant reductions in PaO2/FiO2. Depleting anti-col(V) Abs before transfer demonstrated that IgG2c was a major subtype mediating injury. Confocal microscopy revealed strong apical col(V) expression on lung epithelial, but not endothelial cells; which was consistent with the ability of col(V) immune serum to induce complement-dependent cytotoxicity only in the epithelial cells. Examination of plasma from patients with or without PGD revealed that higher levels of preformed anti-col(V) Abs were strongly associated with PGD development. This study demonstrates a major role for anti-col(V) humoral immunity in PGD, and identifies the airway epithelium as a target in PGD.
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 Grants HL081350, HL60797, and HL/Al67177 (to D.S.W.), HL 077328 (to I.P.), HL087115 and HL081619 (to J.D.C.), AI048624 and AI066219 (to W.B.), and GM71679 and AR53815 (to D.S.G.) from the National Institutes of Health, and a Department of Veterans Affairs Research grant (to D.B.B.).
2 T.I. and A.P. were co-first authors.
3 J.D.C. and D.S.W. were co-senior authors.
4 Address correspondence and reprint requests to Dr. David S. Wilkes, Center for Immunobiology, Van Nuys Medical Science Building, Room MS224, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202. E-mail address: dwilkes{at}iupui.edu
5 Abbreviations used in this paper: BOS, bronchiolitis obliterans syndrome; PGD, primary graft dysfunction; col(V), type V collagen; HEL, hen egg lysozyme; BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis; IPAH, idiopathic pulmonary arterial hypertension.
6 The online version of this article contains supplemental material.
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