Mechanistic link between bombesin‐like peptide (BLP) and the adaptive immune system.

Abstract

Bronchopulmonary dysplasia (BPD) is the leading chronic lung disease in newborns worldwide. Previously, we identified elevated BLP levels in human and baboon infants with BPD. BLP levels were consistently elevated in lung of 125d/PRN baboons with BPD. 2A11, a murine anti-BLP antibody, abrogates BPD lung injury. BLP might modulate adaptive immune responses in BPD. We analyzed thymus and lung using immunofluorescence for markers of dendritic cells (DCs, HLA-DR) and T cells (CD4, CD8) plus thymocyte chemotaxis assays; DR+ cells are reduced to less than 1/10 in thymuses of BPD animals compared to gestational controls (GCs). 2A11 treatment maintained the density of DR+ cells in the thymic cortex at levels comparable to GCs. Immunofluorescence of lung sections shows no difference in density of DR+ cells 125d/PRN animals vs. 2A11-treated 125d/PRN vs. GCs. There are increased CD4+ cells but not CD8+ cells in lung of 125d/14dPRN animals ?MOPC; 2A11-treated 125d/14dPRN animals greatly reduce the number of CD4+ cells in the lung interstitium. There are significantly fewer DR+ cells in lungs of 2A11-treated 125d/14dPRN animals vs. 125d/PRN given MOPC21. Rare DCs are observed in lungs of 25d/21dPRN animals or normal term controls. Next, we tested thymocytes in a migration assay in vitro using BLP ?LPS (1 μg/ml) endotoxin priming. BLP elicits significant chemotaxis of untreated thymocytes from 125d GCs, but neither 140d GCs nor 2A11-treated BPD animals. In the presence of LPS, BLP is also chemotactic for thymocytes from 140d GCs and 2A11-treated 125d/PRN animals. These observations suggest that BLP may promote thymocyte migration to the lung, possible involving transient DR+ cells or CD4+ cells. Thus, BLP may be a mechanistic link between altered adaptive immunity and chronic inflammatory lung diseases. Supported by NIH grants UO1-HL52638 (MES), HL52636 (BPD Resource Ctr.) and P51RR13986 (facility support at SFBR).