THYMIC ABNORMALITIES AND ENHANCED APOPTOSIS OF THYMOCYTES AND BONE-MARROW CELLS IN TRANSGENIC MICE OVEREXPRESSING CU ZN-SUPEROXIDE DISMUTASE - IMPLICATIONS FOR DOWN-SYNDROME/

The copper-zinc superoxide dismutase (CuZnSOD) gene resides on chromos ome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic CuZnSOD mice with elevated levels of CuZnSOD were used to determine w hether, as in DS, overexpression of CuZnSOD was also associated with t hymus and bone marrow abnormalities. Three independently derived trans genic CuZnSOD strains had abnormal thymi showing diminution of the cor tex and loss of corticomedullary demarcation, resembling thymic defect s in children with DS. Transgenic CuZnSOD mice were also more sensitiv e than control mice to in vivo injection of lipopolysaccharide (LPS), reflected by an earlier onset and enhanced apoptotic cell death in the thymus. This higher susceptibility to LPS-induced apoptosis was assoc iated with an increased production of hydrogen peroxide and a higher d egree of lipid peroxidation. When cultured under suboptimal concentrat ions of interleukin 3 or in the presence of tumour necrosis factor, bo ne marrow cells from transgenic CuZnSOD mice produced 2- to 3-fold les s granulocyte and macrophage colonies than control. The results indica te that transgenic CuZnSOD mice have certain thymus and bone marrow ab normalities which are similar to those found in DS patients, and that the defects are presumably due to an increased oxidative damage result ing in enhanced cell death by apoptosis.