title: Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation.
abstract: Over one-third of lung recipients have preexisting antibodies against lung-restricted antigens: collagen (Col) type V and K-α1 tubulin (KAT). Although clinical studies have shown association of these antibodies with primary graft dysfunction (PGD), their biological significance remains unclear. We tested whether preexisting lung-restricted antibodies can mediate PGD and prevent allotolerance. A murine syngeneic (C57BL/6) or allogeneic (C57BL/6 to BALB/c) left lung transplantation model was used. Rabbit polyclonal antibodies were produced against KAT and Col-V and injected pretransplantation. T cell frequency was analyzed using enzyme-linked immunospot, whereas alloantibodies were determined using flow cytometry. Wet:dry ratio, arterial oxygenation, and histology were used to determine PGD. Preexisting Col-V or KAT, but not isotype control, antibodies lead to dose-dependent development of PGD after syngeneic lung transplantation, as evidenced by poor oxygenation and increased wet:dry ratio. Histology confirmed alveolar and capillary edema. The native right lung remained unaffected. Epitope spreading was observed where KAT antibody treatment led to the development of IL-17-producing CD4+T cells and humoral response against Col-V, or vice versa. In contrast, isotype control antibody failed to induce Col-V- or KAT-specific cellular or humoral immunity. In addition, none of the mice developed immunity against a non-lung antigen, collagen type II. Preexisting lung-restricted antibodies, but not isotype control, prevented development of allotolerance using the MHC-related 1 and cytotoxic T-lymphocyte-associated protein 4-Ig regimen. Lung-restricted antibodies can induce both early and delayed lung graft dysfunction. These antibodies can also cause spreading of lung-restricted immunity and promote alloimmunity. Antibody-directed therapy to treat preexisting lung-restricted antibodies might reduce PGD after lung transplantation.
authors.affiliation: Department of 1 Surgery.
authors.forename: Ankit
authors.initials: A
authors.lastname: Bharat
authors.affiliation: Department of 1 Surgery.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chiu
authors.affiliation: Department of 1 Surgery.
authors.forename: Zhikun
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of 1 Surgery.
authors.forename: Haiying
authors.initials: H
authors.lastname: Sun
authors.affiliation: 2 Pathology, and.
authors.forename: Anjana
authors.initials: A
authors.lastname: Yeldandi
authors.affiliation: Department of 1 Surgery.
authors.forename: Malcolm M
authors.initials: MM
authors.lastname: DeCamp
authors.affiliation: 3 Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.affiliation: 3 Internal Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: 4 Norton Thoracic Institute, St. Joseph's Hospital, Phoenix, Arizona.
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
keywords: autoimmunity; lung transplant; primary graft dysfunction; rejection