title: Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection.
abstract: Alloimmunity to mismatched donor HLA-Ags and autoimmunity to self-Ags have been hypothesized to play an important role in immunopathogenesis of chronic rejection of transplanted organs. However, it is not known what role, if any, alloimmune response plays in inducing autoimmunity. To test whether Ab-developed posttransplantation to mismatched donor MHC induces autoimmunity and chronic rejection, we developed a murine model wherein anti-MHC class I Abs or control (C1.18.4/anti-keratin) were administered intrabronchially into native lungs. Animals receiving anti-MHC class I, but not control Abs, developed marked cellular infiltration around vessels and bronchiole of lung by day 15, followed by epithelial hyperplasia, fibrosis, and occlusion of the distal airways similar to chronic rejection following human lung transplantation. Lungs of mice receiving anti-MHC class I showed increased expression of chemokines, their receptors, and growth factors, and induced IL-17 as well as de novo Abs to self-Ags, K-alpha1 tubulin, and collagen V. IL-17 neutralization by anti-IL-17 resulted in reduction of autoantibody and lesions induced by anti-MHC class I Abs. Thus, our results indicate that Abs to donor MHC can induce autoimmunity, mediated by IL-17, which plays a pivotal role in chronic rejection postlung transplantation. Therefore, approaches to prevent autoimmunity should be considered for the treatment of chronic rejection postlung transplantation.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Fukami
authors.forename: Sabarinathan
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Deepti
authors.initials: D
authors.lastname: Saini
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.forename: William
authors.initials: W
authors.lastname: Chapman
authors.forename: G Alexander
authors.initials: GA
authors.lastname: Patterson
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D001666:Binding Sites, Antibody; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002908:Chronic Disease; D005355:Fibrosis; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006183:H-2 Antigens / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D006965:Hyperplasia; D007111:Immunity, Cellular; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D007442:Intubation, Intratracheal; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013577:Syndrome
chemical_list: D001323:Autoantibodies; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D020381:Interleukin-17