title: Association of Local Intrapulmonary Production of Antibodies Specific to Donor Major Histocompatibility Complex Class I With the Progression of Chronic Rejection of Lung Allografts.
abstract: Antibody-mediated rejection may lead to chronic lung allograft dysfunction, but antibody-mediated rejection may develop in the absence of detectable donor-specific antibody (DSA) in recipient serum. This study investigated whether humoral immune responses develop not only systemically but locally within rejected lung allografts, resulting in local production of DSA.
  
  
  
  Lewis rats received orthotopic left lung transplantation from Lewis (syngeneic control) or Brown-Norway (major histocompatibility complex-mismatched allogeneic) donor rats. Rats that underwent allogeneic lung transplantation were subsequently administered cyclosporine until day 14 (short immunosuppression) or day 35 (long immunosuppression). The lung grafts and spleens of recipient animals were tissue cultured for 4 days, and the titer of antibody against donor major histocompatibility complex molecules was assayed by flow cytometry. Explanted lung grafts were also evaluated pathologically.
  
  
  
  By day 98, DSA titers in supernatants of lung graft (P = 0.0074) and spleen (P = 0.0167) cultures, but not serum, from the short immunosuppression group were significantly higher than titers in syngeneic controls. Cultures and sera from the long immunosuppression group showed no production of DSA. Microscopically, the lung grafts from the short immunosuppression group showed severe bronchiole obliteration and parenchymal fibrosis, along with lymphoid aggregates containing T and B cells, accompanying plasma cells. These findings suggestive of local humoral immune response were not observed by days 28 and 63.
  
  
  
  DSA can be locally produced in chronically rejected lung allografts, along with intragraft immunocompetent cells. Clinical testing of DSA in serum samples alone may underestimate lung allograft dysfunction.
authors.affiliation: 1 Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 2 Department of Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan. 3 Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Ei
authors.initials: E
authors.lastname: Miyamoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Motoyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoyama
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.forename: Kei
authors.initials: K
authors.lastname: Shikuma
authors.forename: Terumasa
authors.initials: T
authors.lastname: Sowa
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshizawa
authors.forename: Masao
authors.initials: M
authors.lastname: Saito
authors.forename: Akihiro
authors.initials: A
authors.lastname: Takahagi
authors.forename: Satona
authors.initials: S
authors.lastname: Tanaka
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Keiji
authors.initials: K
authors.lastname: Ohata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hijiya
authors.forename: Toyofumi F
authors.initials: TF
authors.lastname: Chen-Yoshikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D005434:Flow Cytometry; D006084:Graft Rejection / Q000175:diagnosis / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007518:Isoantibodies / Q000378:metabolism*; D008168:Lung / Q000276:immunology*; D016040:Lung Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology
chemical_list: D015415:Biomarkers; D015395:Histocompatibility Antigens Class I; D007518:Isoantibodies