INCREASED MORTALITY AND IMPAIRED CLONAL DELETION AFTER STAPHYLOCOCCAL-ENTEROTOXIN-B INJECTION IN OLD MICE - RELATION TO CYTOKINES AND NITRIC-OXIDE PRODUCTION

In the present study peripheral T cell tolerance and the occurrence of shock were evaluated in young and old mice after injection of Staphyl ococcal enterotoxin B (SEE). In young mice SEE immunization leads to t olerance based on deletion and anergy of SEE-reactive V beta 8(+) T ce lls. With aging, mice developed resistance to SEE-induced deletion of V beta 8(+) T cells as well as a high sensitivity to toxic shock. Comp ared to young mice, older mice injected with SEE showed increased seru m levels of interferon-gamma (IFN?I), interleukin-2 (IL-2) and IL-4. T hese results were confirmed by reverse transcription-polymerase chain reaction (RT-PCR), as splenic mRNA levels taken 2 h after SEE injectio n showed higher values of IL-2, IL-4, and lFN-gamma in old mice. Ln co ntrast, mRNA levels for Fast and tumour necrosis factor-alpha (TNF-alp ha) were lower. No difference in IL-10 mRNA was found. Compared to you ng mice, old mice showed a high, but statistically not significantly d ifferent (P = 0.20), production of nitric oxide (NO). Blocking of IFN- gamma with antibodies or reducing IFN-gamma by depletion of natural ki ller (NK) cells resulted, respectively, in a complete or partial prote ction against mortality in aged mice. Suppressing the NO production by the NO synthase inhibitor N-nitro-L-arginine methylester (L-NAME) inc reased the mortality in both young and old mice, and abrogated clonal deletion in the surviving young mice. In conclusion, in young mice NO production is a key factor in the protection against mortality and the development of clonal deletion after SEE injection. The higher mortal ity seen in older mice is mainly related to the elevated production of IFN-gamma and occurs despite a sufficient production of NO. The decre ased clonal deletion of old mice may be related to their decreased exp ression of Fas ligand or TNF-gamma after SEE injection.