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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.

journal_name

Am J Respir Cell Mol Biol

journal_title

American journal of respiratory cell and molecular biology

authors

Bharat A,Chiu S,Zheng Z,Sun H,Yeldandi A,DeCamp MM,Perlman H,Budinger GR,Mohanakumar T

doi

10.1165/rcmb.2016-0077OC

subject

Has Abstract

pub_date

2016-10-01 00:00:00

pages

532-541

issue

eissn

1044-1549

issn

1535-4989

journal_volume

pub_type

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Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation.