Understanding asthma pathogenesis
Asthma is the most frequent cause of pediatric emergency room visits in the US and is increasing in frequency. Two studies in the Division used mouse models to increase understanding of asthma pathogenesis. Ian Lewkowich, PhD, and colleagues studied cockroach frass, a particularly important allergen in the inner city (J Innate Immunity. 2011. 3: 167-179.). They demonstrated that this allergen promotes the development of asthma by inducing innate immune cells to recruit and activate antigen-presenting myeloid dendritic cells to stimulate CD4+ T cells to produce the Th2 and Th17 cytokines that synergistically induce the inflammatory and functional abnormalities characteristic of asthma. Fred Finkelman, MD, and colleagues demonstrated that direct IL-4 and IL-13 effects on airway smooth muscle cells induce a small set of muscle-associated proteins that stimulate the airway hyperresponsiveness to irritating and neural stimulation, the defining characteristic of human asthma (J. Exp. Med. 2011. 208:853-67). Both of these observations suggest novel therapeutic interventions.
Treatment of Hemophagocytic lymphohistiocytosis (HLH)
HLH is an infection- and inflammation-associated form of anemia in which hyper-activated macrophages cause anemia by ingesting erythrocytes. This disease, which occurs most frequently in children who have a genetic defect in perforin-mediated killing of infected cells, can be lethal and has been difficult to treat. Michael Jordan and collaborators have now shown that treatment with the anti-lymphocyte monoclonal antibody, alemtuzumab, can help to control HLH that has been refractory to conventional therapy (Pediatr Blood Cancer. 2012, online April 22, 2012).
Pathogenesis of transfusion-related acute lung injury (TRALI)
TRALI, the leading cause of death from blood transfusion in developed countries, can be mediated by antibodies to major histocompatibility antigens in transfused blood products that induce a pulmonary vascular leak syndrome. Fred Finkelman, MD, and colleagues developed a mouse model of this disorder and used it to show that these antibodies cause an ultramicroscopic vascular endothelial lesion by binding to vascular endothelial cells and activating complement. This leads to the production of C5a, which attracts macrophages and monocytes to the lungs and induces them to produce the reactive oxygen intermediates that are the proximate cause of the vascular endothelial damage. This damage induces the disease symptoms by allowing fluid to leak from capillaries into the lungs, causing dyspnea and hypoxemia (J. Exp. Med. 2011. 208:2525-44.).These observations should promote the development of better ways to prevent TRALI.
