Published ahead of print on March 30, 2006, doi:10.1164/rccm.200511-1784OC Am. J. Respir. Crit. Care Med., Volume 174, Number 1, July 2006, 75-83 A more recent version of this article appeared on July 1, 2006
Submitted on November 21, 2005 Accelerated Thymic Maturation and Autoreactive T-Cells in Bronchopulmonary DysplasiaDennis Rosen1,1 Departments of Medicine and Pathology, Division of Pulmonary Medicine, Children's and Brigham and Women's Hospitals, and Harvard Medical School, Boston, MA, USA, 2 Department of Pathology, Duke University Medical Center, Durham, NC, USA, 3 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 4 Departments of Pathology, Children's and Brigham and Women's Hospitals, and Harvard Medical School, Boston, MA, USA, 5 Department of Pathology, Duke University Medical Center, Durham, NC, USA; Departments of Pathology, Children's and Brigham and Women's Hospitals, and Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: mary.sunday{at}duke.edu.
Rationale: Bronchopulmonary dysplasia, 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 bronchopulmonary dysplasia in two baboon models. The role of adaptive immunity in bronchopulmonary dysplasia 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 [TdT], proliferating cell nuclear antigen, CD4, and CD8). Thymic cortical epithelial cells (nurse cells) were studied using HLA-DR and PGP9.5 as markers. Functional analysis was carried out 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 TdT-positive prothymocytes and thymocyte proliferation. BPD animals have increased CD4+ cells in thymic cortex and lung interstitium, which are reduced by 2A11. Conversely, cortical PGP9.5/HLA-D-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 less to autologous lung, BPD thymocytes and splenocytes are phythemagglutinin/ionomycin-unresponsive and yet react strongly to autologous lung. 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: bombesin, thymic nurse cells, mixed lymphocyte reaction, immunohistochemistry, animal model,
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