Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection

Ankit Bharat, Elbert Kuo, Nancy Steward, Aviva Aloush, Ramsey Hachem, Elbert P. Trulock, G. Alexander Patterson, Bryan F. Meyers, T. Mohanakumar*

*Corresponding author for this work

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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)-γ 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 (PGD1-3) 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 (PGD0). On serial analysis, PGD1-3 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 (PGD1-3 patients 48% versus PGD0 39.6%, p = 0.6). Furthermore, PGD1-3 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]. 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.

Original languageEnglish (US)
Pages (from-to)189-197
Number of pages9
JournalAnnals of Thoracic Surgery
Volume86
Issue number1
DOIs
StatePublished - Jul 1 2008

Fingerprint

Primary Graft Dysfunction
Allografts
HLA Antigens
Lung
Prostaglandins D
Isoantibodies
Interferons
Cytokines
Inflammation
T-Lymphocytes
Enzyme-Linked Immunospot Assay
Lung Injury
Interleukin-12
Serum
Interleukin-1
Chemokines
Interleukin-2

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Bharat, Ankit ; Kuo, Elbert ; Steward, Nancy ; Aloush, Aviva ; Hachem, Ramsey ; Trulock, Elbert P. ; Patterson, G. Alexander ; Meyers, Bryan F. ; Mohanakumar, T. / Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection. In: Annals of Thoracic Surgery. 2008 ; Vol. 86, No. 1. pp. 189-197.
@article{764a4ffa20e84b70a8f6081f8696affc,
title = "Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection",
abstract = "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)-γ 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 (PGD1-3) 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 (PGD0). On serial analysis, PGD1-3 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 (PGD1-3 patients 48{\%} versus PGD0 39.6{\%}, p = 0.6). Furthermore, PGD1-3 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]. 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.",
author = "Ankit Bharat and Elbert Kuo and Nancy Steward and Aviva Aloush and Ramsey Hachem and Trulock, {Elbert P.} and Patterson, {G. Alexander} and Meyers, {Bryan F.} and T. Mohanakumar",
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Bharat, A, Kuo, E, Steward, N, Aloush, A, Hachem, R, Trulock, EP, Patterson, GA, Meyers, BF & Mohanakumar, T 2008, 'Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection', Annals of Thoracic Surgery, vol. 86, no. 1, pp. 189-197. https://doi.org/10.1016/j.athoracsur.2008.03.073

Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection. / Bharat, Ankit; Kuo, Elbert; Steward, Nancy; Aloush, Aviva; Hachem, Ramsey; Trulock, Elbert P.; Patterson, G. Alexander; Meyers, Bryan F.; Mohanakumar, T.

In: Annals of Thoracic Surgery, Vol. 86, No. 1, 01.07.2008, p. 189-197.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Immunological Link Between Primary Graft Dysfunction and Chronic Lung Allograft Rejection

AU - Bharat, Ankit

AU - Kuo, Elbert

AU - Steward, Nancy

AU - Aloush, Aviva

AU - Hachem, Ramsey

AU - Trulock, Elbert P.

AU - Patterson, G. Alexander

AU - Meyers, Bryan F.

AU - Mohanakumar, T.

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 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)-γ 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 (PGD1-3) 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 (PGD0). On serial analysis, PGD1-3 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 (PGD1-3 patients 48% versus PGD0 39.6%, p = 0.6). Furthermore, PGD1-3 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]. 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.

AB - 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)-γ 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 (PGD1-3) 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 (PGD0). On serial analysis, PGD1-3 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 (PGD1-3 patients 48% versus PGD0 39.6%, p = 0.6). Furthermore, PGD1-3 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]. 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.

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DO - 10.1016/j.athoracsur.2008.03.073

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JO - Annals of Thoracic Surgery

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