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)-gamma 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)-1 beta, IL-2, IFN-gamma, 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) 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.
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)-gamma 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)-1 beta, IL-2, IFN-gamma, 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) 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.
Authors: Jason D Christie; Martin Carby; Remzi Bag; Paul Corris; Marshall Hertz; David Weill Journal: J Heart Lung Transplant Date: 2005-06-04 Impact factor: 10.247
Authors: M Melter; A Exeni; M E Reinders; J C Fang; G McMahon; P Ganz; W W Hancock; D M Briscoe Journal: Circulation Date: 2001-11-20 Impact factor: 29.690
Authors: J A Belperio; M P Keane; M D Burdick; J P Lynch; Y Y Xue; A Berlin; D J Ross; S L Kunkel; I F Charo; R M Strieter Journal: J Clin Invest Date: 2001-08 Impact factor: 14.808
Authors: S Sundaresan; T Mohanakumar; M A Smith; E P Trulock; J Lynch; D Phelan; J D Cooper; G A Patterson Journal: Transplantation Date: 1998-03-15 Impact factor: 4.939
Authors: M A Smith; S Sundaresan; T Mohanakumar; E P Trulock; J P Lynch; D L Phelan; J D Cooper; G A Patterson Journal: J Thorac Cardiovasc Surg Date: 1998-11 Impact factor: 5.209
Authors: Peter H Hagedorn; Christopher M Burton; Eli Sahar; Eytan Domany; Irun R Cohen; Henrik Flyvbjerg; Martin Iversen Journal: Immunology Date: 2010-11-11 Impact factor: 7.397
Authors: Zhikun Zheng; Stephen Chiu; Mahzad Akbarpour; Haiying Sun; Paul A Reyfman; Kishore R Anekalla; Hiam Abdala-Valencia; Daphne Edgren; Wenjun Li; Daniel Kreisel; Farida V Korobova; Ramiro Fernandez; Alexandra McQuattie-Pimentel; Zheng J Zhang; Harris Perlman; Alexander V Misharin; G R Scott Budinger; Ankit Bharat Journal: Sci Transl Med Date: 2017-06-14 Impact factor: 17.956
Authors: Y Liu; W Li; H P Luehmann; Y Zhao; L Detering; D H Sultan; H-M Hsiao; A S Krupnick; A E Gelman; C Combadiere; R J Gropler; S L Brody; D Kreisel Journal: Am J Transplant Date: 2016-07-14 Impact factor: 8.086
Authors: J M Diamond; S M Kawut; D J Lederer; V N Ahya; B Kohl; J Sonett; S M Palmer; M Crespo; K Wille; V N Lama; P D Shah; J Orens; S Bhorade; A Weinacker; E Demissie; S Bellamy; J D Christie; L B Ware Journal: Am J Transplant Date: 2011-02-07 Impact factor: 8.086
Authors: Lisa Rancan; Sergio D Paredes; Luis Huerta; Javier Casanova; Jorge Guzmán; Ignacio Garutti; Federico González-Aragoneses; Carlos Simón; Elena Vara Journal: Lung Date: 2017-04-21 Impact factor: 2.584
Authors: Hidemi Suzuki; Mark E Lasbury; Lin Fan; Ragini Vittal; Elizabeth A Mickler; Heather L Benson; Rebecca Shilling; Qiang Wu; Daniel J Weber; Sarah R Wagner; Melissa Lasaro; Denise Devore; Yi Wang; George E Sandusky; Kelsey Lipking; Pankita Pandya; John Reynolds; Robert Love; Thomas Wozniak; Hongmei Gu; Krista M Brown; David S Wilkes Journal: J Immunol Date: 2013-09-16 Impact factor: 5.422
Authors: Joshua M Diamond; Tatiana Akimova; Altaf Kazi; Rupal J Shah; Edward Cantu; Rui Feng; Matthew H Levine; Steven M Kawut; Nuala J Meyer; James C Lee; Wayne W Hancock; Richard Aplenc; Lorraine B Ware; Scott M Palmer; Sangeeta Bhorade; Vibha N Lama; Ann Weinacker; Jonathan Orens; Keith Wille; Maria Crespo; David J Lederer; Selim Arcasoy; Ejigayehu Demissie; Jason D Christie Journal: Am J Respir Crit Care Med Date: 2014-03-01 Impact factor: 21.405