Published ahead of print on March 30, 2006, doi:10.1164/rccm.200511-1784OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200511-1784OC
Accelerated Thymic Maturation and Autoreactive T Cells in Bronchopulmonary DysplasiaDivision of Pulmonary Medicine, Departments of Medicine and Pathology, Children's and Brigham and Women's Hospitals, and Harvard Medical School, Boston, Massachusetts; Department of Pathology, Duke University Medical Center, Durham, North Carolina; and National Cancer Institute, National Institutes of Health, Cell and Cancer Biology Branch, Bethesda, Maryland Correspondence and requests for reprints should be addressed to Mary E. Sunday, M.D., Ph.D., Duke University Medical Center, Department of Pathology, Box 3712, Durham, NC 27710. E-mail: mary.sunday{at}duke.edu Rationale: Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesin-like peptides shortly after birth mediate lung injury: anti-bombesin antibody 2A11 protects against BPD in two baboon models. The role of adaptive immunity in BPD has not been explored previously. Objectives: Our goal was to test the hypothesis that thymic architecture and/or T-cell function is altered with BPD, leading to autoimmunity and immunodeficiency. Methods: Thymic structure was analyzed by histopathology of thymic architecture and immunohistochemistry for thymic maturation markers (terminal deoxynucleotidyl transferase, proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and protein gene product 9.5 as markers. Functional analysis was performed with "mixed lymphocyte reaction" of thymocyte or splenocyte responder cells with autologous lung cells as the stimulators. Measurements and Main Results: 2A11 treatment attenuates thymic cortical involution in BPD animals, sustaining terminal deoxynucleotidyl transferase–positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4+ cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical protein gene product 9.5/HLA-DR–positive thymic nurse cells are depleted in BPD animals, but are preserved by 2A11-treatment. Whereas fetal thymocytes and splenocytes respond to phythemagglutinin/ionomycin and to a lesser extent, to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive, and yet react strongly to autologous lung. The 2A11 normalizes these responses. Conclusions: These observations suggest that bombesin-like peptides mediate premature thymic maturation and thymic nurse-cell depletion, leading to autoreactive T cells that could contribute to lung injury.
Key Words: animal model • bombesin • immunohistochemistry • mixed lymphocyte reaction • thymic nurse cells This article has been cited by other articles:
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