Accelerated thymic maturation and autoreactive T cells in bronchopulmonary dysplasia.
BACKGROUND
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.


OBJECTIVE
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.


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.
Division of Pulmonary Medicine, Department of Medicine, Children's and Brigham and Women's Hospitals, and Harvard Medical School, Boston, Massachusetts, USA.
Dennis
D
Rosen
Jong-Hwan
JH
Lee
Frank
F
Cuttitta
Fatema
F
Rafiqi
Simone
S
Degan
Mary E
ME
Sunday
D000818:Animals; D000831:Animals, Newborn; D001997:Bronchopulmonary Dysplasia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007959:Lymphocyte Culture Test, Mixed; D010215:Papio; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D018809:Proliferating Cell Nuclear Antigen; D004253:DNA Nucleotidylexotransferase