Critical role for selectin receptor:ligand interactions in the development of IPS following allogeneic BMT (145.32)

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Abstract Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication of allogeneic BMT and limits successful outcomes. The pathophysiology of IPS involves the release of soluble inflammatory proteins and the recruitment of donor lymphoid and myeloid effectors into the lung. The entry of leukocytes into inflamed tissue is mediated by several molecules that are orchestrated in a sequential manner. We used well-established mouse BMT models to investigate the role of selectin (sel) receptor:ligand interactions in the development of IPS. Firstly, E and P sel ligands are up-regulated on donor T cells when activated by host APCs in vitro. Next, we found that sel receptor (mRNA) and ligand (protein) expression is significantly increased in the lungs of allo-BMT recipients during the development of IPS. BMT using donor cells deficient in E and P sel ligands resulted in a significant reduction in lung inflammation (cellularity, pathology, cytokines), and mixing studies uncovered a contribution to cells of both lymphoid and myeloid lineage. Experiments using isolated MHC class I or class II disparate strain combinations revealed a more significant effect on donor CD4+ vs. CD8+ T cells. Finally absence of E and P sel in BMT recipient mice conferred near complete protection from IPS especially during CD4+ mediated disease. These data demonstrate a critical role for selectin receptor:ligand interactions in the pathogenesis of IPS and uncover novel strategies to regulate disease severity.