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J. Maxwell Chamberlain Memorial Paper for General Thoracic Surgery

Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection

^a Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
^b Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
^d Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, Missouri

Accepted for publication March 28, 2008.

^_* Address correspondence to Dr Mohanakumar, Washington University School of Medicine, Department of Surgery, Box 8109-3328 CSRB, 660 S Euclid Ave, St. Louis, MO 63110 (Email: kumart{at}wustl.edu).

Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008. Winner of the J. Maxwell Chamberlain Memorial Award for General Thoracic Surgery.

Background: 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.

Methods: 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)- ELISPOT. Serum levels of 25 cytokines and chemokines were measured using LUMINEX.

Results: 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-, and IL-12 in the sera during the early posttransplant period compared with patients with PGD grade 0 (PGD₀). On serial analysis, PGD_1-3 patients revealed increased development of de novo anti-HLA-II (5 years: 52.2% versus PGD₀ 13.5%, p = 0.008). However, no difference was found in anti-HLA-I alloantibody development (PGD_1-3 patients 48% versus PGD₀ 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) x 10^–6 versus (23.6 ± 15.93) x 10^–6, p = 0.003].

Conclusions: 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.