T cell senescence is a majOr factor associated with the development of age-related tumOrs and autoimmune disease. To preVent immune senescence caused by a decreased Fas-mediated apoptosis, Charles River CD-I mouse strain was used as the background genetic source to construct a fas transgenic mouse line bearing a CD2 promoter and enhancer to correct Fas expression in the aged T cells of CD2-fas transgenic (Tr+) mice. Although immune senescence was prevented, these Tr+ mice developed excessive acute phase response and elevated renal amyloid A amyloidosis. The hypothesis of the present proposal substantiates the concept that an increased Fas-mediated apoptosis in aged T cells may be a risk factor to potentiate age- related increased acute-phase response and septic shock syndrOme, and that an alteration of Fas-mediated apoptosis pathway may be an important pathogenic mechanism of amyloidosis in the aged mice. To further understand the pathogenesis of Fas-mediated apoptosis, amyloidosis, and acute-phase response in aged mice, the following questions will be addressed in the present proposal:I. Determine the immunologic factors involved in the prolonged acute-phase response and SAA production in the aged CD2-fas transgenic mice. 2. Determine the effect of aging and CD2-fas transgene on the interaction of T cells and hepatocytes. 3. Determine whether Fas- mediated apoptosis in the T cells and in the hepatocytes is related to the increased acute-phase response and SAA synthesis in aged Tr+ mice. Results from the present study will provide new insights to the pathogenesis of aging, including understanding the mechanisms of immune senescence, amyloidosis, and acute phase-induced shock. These understandings will further help to design strategies to prevent amyloidosis and septic shock, as well as to devise methods for developing both effective and safe immunotherapy for aged subjects.
|Hsu, H C; Mountz, J D; Zhou, T (1999) Regulation of Fas-mediated apoptosis in CD2-fas transgenic mice. Int Rev Immunol 18:309-27|