Gene targeting by homologous recombination can be used to activate or inactivate cellular genes in eukaryotic cells. The objective of this project is to alter the functional status of genes that control growth and maturation of specific tissues and study the biological consequences of these molecularly defined alterations. We have initiated this program with an investigation to delineate specific roles of transforming growth factor beta-1 (TGF-beta 1). We have generated TGF-beta 1 knockout mice using gene targeting technique. These mice are deficient in this growth factor. After normal growth for the first two weeks, they develop a rapid wasting syndrome and die as early as three weeks of age. Histopathological examination revealed multifocal inflammatory response with massive infiltration of lymphocytes and macrophages in many organs, but primarily in heart and lungs. Further examination indicated that onset of multifocal inflammation follows elevated expression of major histocompatibility Class I and II genes and increased adhesion of leukocytes to endothelium of blood vessels in the affected tissues. Increased adhesion of leukocytes in these animals was associated with higher expression of VLA4 cell surface markers in the leukocytes. Fibronectin peptide treatment of the knock-out mice blocked inflammation, moderated the body weight and restored homeostatic regulation of immune cell proliferation and inflammation. The mice have anti-DNA and other autoantibodies in the serum. When TGF-beta 1 null bone marrow is transplanted into normal recipients, the recipients develop similar autoantibodies as the knockout mice and most recipients show signs of esophagitis. Collectively, these data indicate that autoimmune mechanisms play a role in the etiology of the inflammatory process in these mice.
