Antibodies to Self-Antigens Predispose to Primary Lung Allograft Dysfunction and Chronic Rejection

doi:10.1016/j.athoracsur.2010.06.009

The Annals of Thoracic Surgery

Volume 90, Issue 4, October 2010, Pages 1094-1101

Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010.

https://doi.org/10.1016/j.athoracsur.2010.06.009 Get rights and content

Background

Primary graft dysfunction (PGD) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. Here, we report that preformed antibodies to self-antigens increase PGD risk and promote BOS.

Methods

Adult lung transplant recipients (n = 142) were included in the study. Primary graft dysfunction and BOS were diagnosed based on International Society for Heart and Lung Transplantation guidelines. Antibodies to self-antigens k-alpha-1 tubulin, collagen type V, and collagen I were quantitated using standardized enzyme-linked immunosorbent assays, and cytokines were analyzed using Luminex immunoassays (Biosource International, Camirillo, CA). Human leukocyte antigen (HLA) antibodies were measured using Flow-PRA (One Lambda, Canoga Park, CA).

Results

Lung transplant recipients with pretransplant antibodies to self-antigens had increased risk of PGD (odds ratio 3.09, 95% confidence interval: 1.2 to 8.1, p = 0.02) compared with recipients without. Conversely, in patients with PGD, 34.7% were positive for pretransplant antibodies whereas in the PGD negative group, only 14.6% had antibodies (p = 0.03). Antibody positive patients demonstrated high levels of proinflammatory cytokines interleukin (IL)-1β (2.1-fold increase), IL-2 (3.0), IL-12 (2.5), IL-15 (3.0), and chemokines interferon-inducible protein-10 (3.9) and monocyte chemotactic protein-1 (3.1; p < 0.01 for all). On 5-year follow-up, patients without antibodies showed greater freedom from development of HLA antibodies compared with patients who had antibodies (class I: 67% versus 38%, p = 0.001; class II: 71% versus 41%, p < 0.001). Patients with pretransplant antibodies were found to have an independent relative risk of 2.3 (95% confidence interval: 1.7 to 4.5, p = 0.009) for developing BOS.

Conclusions

Presence of antibodies to self-antigens pretransplant increases the risk of PGD immediately after transplant period and BOS on long-term follow-up. Primary graft dysfunction is associated with an inflammatory cascade that augments the alloimmune (anti-HLA) response that predisposes to BOS.

Section snippets

Study Subjects

Adult patients undergoing lung transplantation at Washington University Medical Center, Barnes-Jewish Hospital were prospectively enrolled in the study between 1995 and 2005 after obtaining informed consent, in accordance with a protocol approved by the Institutional Review Board. The peripheral blood mononuclear cells were isolated from heparinized blood by Ficoll-Hypaque density gradient centrifugation (Pharmacia, Stockholm, Sweden), and stored at −135°C. The plasma separated from peripheral

Pretransplant Antibodies and Risk of PGD

The study included 142 lung transplant patients. The clinical and demographic profile of the recipients and donors is shown in Table 1. Of the patients included in the study, 101 were negative for all antibodies, and 41 had one or more of the three antibodies (Fig 1). There were no significant differences in the clinicodemographic variables between the study groups. We first screened BAL from HLA-antibody negative patients with (n = 28) and without PGD (n = 17) for soluble C4d. Patients with

Comment

Land and colleagues [12] initially introduced the concept of “response to injury” hypothesis [13]. They proposed the role for early posttransplant inflammation in increasing allograft immunogenicity and risk for chronic rejection. In human lung transplantation, PGD is known to be a major risk factor for BOS [3]. All grades of PGD (1 to 3) independently increase the risk. The reported incidence of PGD after lung transplantation approaches more than 80% [3]. As PGD is a major risk for BOS, it is

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Original articleGeneral thoracicAntibodies to Self-Antigens Predispose to Primary Lung Allograft Dysfunction and Chronic Rejection

Background

Methods

Results

Conclusions

Section snippets

Study Subjects

Pretransplant Antibodies and Risk of PGD

Comment

J Heart Lung Transplant

Semin Thorac Cardiovasc Surg

Ann Thorac Surg

J Heart Lung Transplant

J Heart Lung Transplant

Am J Transplant

Micron

J Heart Lung Transplant

Hum Immunol

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome

Am J Respir Crit Care Med

Original article
General thoracic
Antibodies to Self-Antigens Predispose to Primary Lung Allograft Dysfunction and Chronic Rejection