Elsevier

The Annals of Thoracic Surgery

Volume 90, Issue 5, November 2010, Pages 1637-1644
The Annals of Thoracic Surgery

Original article
General thoracic
Respiratory Virus-Induced Dysregulation of T-Regulatory Cells Leads to Chronic Rejection

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.2010.06.048Get rights and content

Background

Lower respiratory viral infections predispose to bronchiolitis obliterans syndrome (BOS). In addition, there is emerging evidence to support the role of autoimmunity in the pathogenesis of BOS. Because CD4+CD25+Foxp3+ regulatory T-cells (Treg) control autoimmunity, we tested the hypothesis that respiratory virus-induced Treg dysfunction leads to BOS.

Methods

Treg frequency was monitored using flow cytometry. Apoptosis, cytokines, and antibodies were analyzed using annexin V assay, LUMINEX, and enzyme-linked immunosorbent assay, respectively. Murine studies were performed using the orthotopic tracheal transplant model.

Results

(A) Human studies: Treg troughs (decrease >50% of baseline) were found in 13 (43.3%) of 30 lung transplant recipients. Treg isolated during troughs revealed increased apoptosis (37.8%). Patients with Treg troughs had increased prevalence of antibodies to self-antigens collagen type I (23.1% vs 5.8% pretrough), collagen V (7.7% vs 0%), and k-alpha tubulin (30.7% vs 11.7%, p < 0.01) at 6 months post-trough. Increased number of Treg troughs correlated with more rapid onset of BOS. (B) Murine studies: Infection of tracheal transplant recipients with murine parainfleunza sendai virus led to increased Treg apoptosis (50.5%) in the draining lymph nodes. Vaccination against sendai virus prior to transplant abrogated apoptosis of Treg. In vitro, sendai virus-infected, but not naive, tracheal epithelial cells demonstrated upregulation of FasL (>3.5-fold) and induction of co-cultured Treg apoptosis (5.6-fold increase).

Conclusions

Respiratory viral infections cause Treg apoptosis which leads to the development of de novo autoimmunity that may play a role in the pathogenesis of BOS.

Section snippets

Human Subjects

Blood specimens were collected from patients undergoing lung transplantation and normal volunteers at the Barnes-Jewish Hospital after obtaining informed consent in accordance with a protocol approved by the Institutional Review Board. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized blood by Ficoll-Hypaque density gradient centrifugation, and stored at −135°C. Plasma was stored at −70°C. Bronchiolitis obliterans syndrome was defined according to the standard

Loss of Treg During Respiratory Viral Infections in Human Lung Transplant Recipients

The clinical and demographic profile of study subjects (n = 30) is shown in Table 1. We determined the frequency of Treg in lung transplant recipients at 2 to 4 month intervals using PBMC. The median onset of BOS was 45 months. As shown in Table 2, 13 of the thirty patients (43.3%) revealed a trough as defined by a drop in the frequency of Treg greater than 50% of the baseline, prior to the development of BOS. Of the patients who revealed Treg trough (n = 13), 9 (69.2%) had a single trough, 3

Comment

Bronchiolitis obliterans syndrome remains the major cause of poor long-term lung allograft survival [11, 16]. The development of BOS is highly complex and involves multiple pathways. It is generally believed that both alloimmune dependent and independent pathways contribute to BOS [1]. There is increasing evidence that alterations in pathways responsible for maintenance of peripheral tolerance may play a crucial role in chronic rejection. In support of this, studies have shown that Treg play an

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