Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection

• Published in: The Annals of thoracic surgery Vol. 86; no. 1; pp. 189 - 197
• Main Authors: Bharat, Ankit, Kuo, Elbert, Steward, Nancy, Aloush, Aviva, Hachem, Ramsey, Trulock, Elbert P., Patterson, G. Alexander, Meyers, Bryan F., Mohanakumar, T.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2008
• Subjects: Adult; Age Distribution; Aged; Biomarkers - blood; Bronchiolitis Obliterans - epidemiology; Bronchiolitis Obliterans - etiology; Bronchiolitis Obliterans - immunology; Cardiothoracic Surgery; Chronic Disease; Female; Follow-Up Studies; Graft Rejection - epidemiology; Graft Rejection - immunology; Histocompatibility Testing; HLA Antigens - analysis; HLA Antigens - immunology; Humans; Incidence; Isoantibodies - analysis; Isoantibodies - immunology; Lung Transplantation - adverse effects; Lung Transplantation - immunology; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Assessment; Sex Distribution; Surgery; Time Factors; Tissue Donors; Transplantation, Homologous - adverse effects; Transplantation, Homologous - immunology; 12; IL; APC; HLA-DR; BOS; HLA; PGD; ISHLT; PBMC; human leukocyte antigen; human leukocyte antigen–donor; International Society for Heart and Lung Transplantation; interleukin; antigen presenting cells; peripheral blood mononuclear cell; primary graft dysfunction; broncholitis obliterans syndrome
• ISSN: 0003-4975; 1552-6259; 1552-6259
• DOI: 10.1016/j.athoracsur.2008.03.073

Primary graft dysfunction (PGD) in the immediate post–lung transplant period strongly increases the risk of chronic rejection (broncholitis obliterans syndrome). Here, we hypothesized that PGD-induced inflammation augments alloimmunity, thereby predisposing to broncholitis obliterans syndrome. Primary graft dysfunction and broncholitis obliterans syndrome were diagnosed according to the established International Society for Heart and Lung Transplantation criteria. Anti–human leukocyte antigen (HLA) alloantibodies were analyzed using Flow-PRA. Donor HLA class II–specific T cells were analyzed using interferon (IFN)-γ ELISPOT. Serum levels of 25 cytokines and chemokines were measured using LUMINEX. Of the 127 subjects, 29 (22.8%) had no PGD (grade 0), 42 (33.2%) had PGD-1, 36 (28.3%) had PGD-2, and 20 (15.7%) had PGD-3. Patients with PGD grades 1 to 3 (PGD 1-3) had elevated proinflammatory mediators MCP-1, IP-10, interleukin (IL)-1β, IL-2, IFN-γ, and IL-12 in the sera during the early posttransplant period compared with patients with PGD grade 0 (PGD 0). On serial analysis, PGD 1-3 patients revealed increased development of de novo anti-HLA-II (5 years: 52.2% versus PGD 0 13.5%, p = 0.008). However, no difference was found in anti-HLA-I alloantibody development (PGD 1-3 patients 48% versus PGD 0 39.6%, p = 0.6). Furthermore, PGD 1-3 patients had increased frequency of donor HLA class II–specific CD4 + T cells [(91.4 ± 19.37) × 10 −6 versus (23.6 ± 15.93) × 10 −6, p = 0.003]. Primary graft dysfunction induces proinflammatory cytokines that can upregulate donor HLA-II antigens on the allograft. Increased donor HLA-II expression along with PGD-induced allograft inflammation promotes the development of donor specific alloimmunity. This provides an important mechanistic link between early posttransplant lung allograft injury and reported association with broncholitis obliterans syndrome.