TY - JOUR
T1 - Respiratory virus-induced dysregulation of T-regulatory cells leads to chronic rejection
AU - Bharat, Ankit
AU - Kuo, Elbert
AU - Saini, Deepti
AU - Steward, Nancy
AU - Hachem, Ramsey
AU - Trulock, Elbert P.
AU - Patterson, G. Alexander
AU - Meyers, Bryan F.
AU - Mohanakumar, Thalachallour
N1 - Funding Information:
This work was supported by American Recovery and Reinvestment Act Award HL056643 from the National Institutes of Health (NIH)-National Heart Lung Blood Institute (T.M.), and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We thank Ms Billie Glascock for assistance in the preparation of this manuscript.
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78049313215&partnerID=8YFLogxK
U2 - 10.1016/j.athoracsur.2010.06.048
DO - 10.1016/j.athoracsur.2010.06.048
M3 - Article
C2 - 20971279
AN - SCOPUS:78049313215
SN - 0003-4975
VL - 90
SP - 1637
EP - 1644
JO - Annals of Thoracic Surgery
JF - Annals of Thoracic Surgery
IS - 5
ER -