We have developed a mouse system by which to track the migration and homing of cells in a setting of bone marrow transplantation (BMT)-induced graft-versushost disease (GVHD) after systemic infusion using enhanced green fluorescence protein (

Idiopathic pneumonia syndrome (IPS) is a significant cause of morbidity and mortality after bone marrow transplantation (BMT) in humans. We developed a murine IPS model in which lethal pre-BMT conditioning and allogeneic T cells results in the recruitment of host monocytes and then donor T cells into the lung by day 7 after BMT, concomitant with development of severe lung dysfunction. We reported the T cell-dependent production of the T cell-attracting chemokine macrophage inflammatory protein-1␣ (MIP-1␣) in the lungs of such recipient mice. We reasoned that MIP-1␣ might be a critical mediator of IPS.

Following allogeneic bone marrow transplantation (alloBMT), idiopathic pneumonia syndrome (IPS) and graft-versus-host disease (GVHD) caused by donor cell alloreactivity remain major obstacles to a successful outcome. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is involved in regulating lymphohematopoietic cell migration and facilitating T-cell responses. To determine whether ICAM-1 expression in the host would affect IPS or GVHD tissue injury responses, ICAM-1(-/-) mice were compared with ICAM-1(+/+) controls. ICAM-1(-/-) recipients did not exhibit the manifestations of IPS injury such as an increase in lung weights nor decreased lung function. The influx of T cells, macrophages, and neutrophils was dramatically dampened as was the production of the inflammatory cytokines interferon-gamma and tumor necrosis factor alpha and the chemokines monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and lymphotactin, normally upregulated in the lung during IPS. In contrast, systemic levels of these mediators were unaffected and GVHD-induced lesions in the liver and colon did not differ in severity regardless of ICAM-1 expression. GVHD-mediated mortality was accelerated in ICAM-1(-/-) recipients at doses of allogeneic spleen cells that are otherwise not uniformally lethal. These data implicate ICAM-1 as playing a critical role in the generation of IPS; therefore, ICAM-1 may be a discerning element, segregating IPS from GVHD injury post-alloBMT.