Accelerated Thymic Maturation and Autoreactive T Cells in Bronchopulmonary Dysplasia

Abstract

Rationale: Bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns triggered by oxygen and barotrauma, is characterized by arrested alveolarization. Increased levels of bombesinlike 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/ionomycinunresponsive, 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.

RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

“…Consistent with GRPR mRNA in PMN, macrophages, and T cells, GRP blockade suppresses acute and chronic inflammation in both O 3 and OVA models. In baboon models of BPD (6,20), GRP blockade normalizes thymic maturation and T cell responses and reduces CD4 + T cells in the pulmonary interstitium (28). GRP blockade could arrest migration of peribronchiolar CD4 + T cells, which contribute to airways inflammation in mice and asthma in humans (51).…”

“…Classical inflammatory responses in asthma include both the innate and adaptive immune systems (2), triggered by allergens, irritants, smoke, viruses, and other agents. GRP induces host responses typical of asthma, including mast cell chemotaxis, macrophage migration, and proliferation of T cells and fibroblasts (27)(28)(29)(30)(31). GRP receptor (GRPR) is expressed by peribronchiolar fibroblasts (32).…”

Early Interstitial Lung Disease in Familial Pulmonary Fibrosis

“…Nonsmoker 5 o, eversmoker 5 x. markers were found in subjects with asymptomatic ILD compared with subjects with normal HRCT scans, and our findings of lymphocyte activation did not appear to be related to a history of active or former smoking. These findings are interesting in light of the experimental evidence suggesting that innate and adaptive immunity have a role in repair of injured lung and the development of pulmonary fibrosis (28)(29)(30). In addition, intrapulmonary infiltrations of activated CD4 T cells in early ILD are consistent with other reports that show the T-cell antigen receptor (TCR) repertoires of lymphocytes within BAL fluid of patients with IPF are highly biased, suggesting an antigen-driven process (31,32).…”

Intraamniotic Lipopolysaccharide Exposure Changes Cell Populations and Structure of the Ovine Fetal Thymus

“…A small thymus size in preterm infants is a strong indicator of other adverse outcomes such as bronchopulmonary dysplasia [17][18][19] and fetal inflammatory response syndrome. 20 Thymic involution in preterm infants is associated with a higher risk for the development of cerebral white matter damage, the major antecedent of cerebral palsy.…”