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)-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: Ankit Bharat, Elbert Kuo, Nancy Steward, Aviva Aloush, Ramsey Hachem, Elbert P Trulock, G Alexander Patterson, Bryan F Meyers, T Mohanakumar
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 86 Issue 1 Pg. 189-95; discussion 196-7 (Jul 2008) ISSN: 1552-6259 [Electronic] Netherlands
• PMID: 18573422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• HLA Antigens
• Isoantibodies

Topics

• Adult
• Age Distribution
• Aged
• Biomarkers (blood)
• Bronchiolitis Obliterans (epidemiology, etiology, immunology)
• Chronic Disease
• Female
• Follow-Up Studies
• Graft Rejection (epidemiology, immunology)
• HLA Antigens (analysis, immunology)
• Histocompatibility Testing
• Humans
• Incidence
• Isoantibodies (analysis, immunology)
• Lung Transplantation (adverse effects, immunology)
• Male
• Middle Aged
• Multivariate Analysis
• Prospective Studies
• Risk Assessment
• Sex Distribution
• Time Factors
• Tissue Donors
• Transplantation, Homologous (adverse effects, immunology)