Blockade of CD40-CD40 ligand interactions protects against radiation-induced pulmonary inflammation and fibrosis

This study investigated whether CD40-CD40 ligand (L) interactions are impor tant in mediating ionizing radiation-induced lung toxicity, Radiotherapy is a key component in the management of malignant diseases and is a condition ing regimen for bone marrow transplantation. Unfortunately, radiation thera py is particularly toxic to the lung, potentially inducing a fatal pneumoni tis and fibrosis, thus limiting its effectiveness. There are no therapies t hat protect against the development of radiation-induced lung toxicity. Usi ng a mouse model of radiation-induced lung toxicity, a monoclonal anti-CD40 L antibody (MR1) that disrupts CD40-CD40L, interactions was tested for the ability to reduce lung injury. C57BL/6 mice were pretreated with either not hing, MR1, or hamster IgG 24 h prior to a single dose of 15 Gray ionizing r adiation to the thorax. During the following 26 weeks, mice continued to re ceive MR1 or hamster IgG twice per week. MR1 protected against death from r adiation pneumonitis and fibrosis and dramatically reduced lung pathology a s evidenced by a limited influx of inflammatory cells, minimal collagen dep osition, and septal thickening MR1 also prevented radiation-induced pulmona ry mastocytosis and blunted expression of cyclooxygenase-2, a proinflammato ry enzyme responsible for prostaglandin synthesis, Disruption of CD40-CD40 interactions may offer a new mode of intervention to protect against radiat ion-induced pulmonary toxicity. (C) 1998 Academic Press.