TRANSFORMING GROWTH-FACTOR-BETA-1 NULL MICE - AN ANIMAL-MODEL FOR INFLAMMATORY DISORDERS

Approximately 40% of transforming growth factor-beta 1 null (knockout) mice generated in our laboratory develop normally to term, but 60% di e in utero. The animals appear normal during the first 2 weeks of life but develop a rapid wasting syndrome and die by 3 to 4 weeks of age. All of the knockout mice have a multifocal inflammatory disease in man y tissues. The heart and lungs are most severely affected. Increased a dhesion of leukocytes to the endothelium of pulmonary veins is the ini tial lesion seen at day 8 postnatally and is soon followed by perivasc ular cuffing as well as inflammatory infiltrates in lung parenchyma. T he lesions in the heart begin as endocarditis and then progress to myo carditis and pericarditis. Within the lung, chronic inflammatory infil trates consist of T and B lymphocytes, including plasma cells, whereas macrophages are the primary inflammatory cell type in the heart. Incr eased expression of major histocompatibility complex class I and II pr oteins in seen in pulmonary vascular endothelium as early as day 8. An immunoblastic response in mediastinal and mandibular lymphnodes and s pleen is also seen. In the absence of any pathogens, this massive infl ammatory disease, together with overexpression of major histocompatibi lity complex class I and II proteins and overproduction of immunoglobu lins by lymphocytes, offers circumstantial evidence for an autoimmune etiology.