Sepsis induces lymphocyte apoptosis and prevention of lymphocyte death may improve the chances of surviving this disorder. We compared the efficacy of a selective caspase-3 inhibitor to a polycaspase inhibitor and to caspase-3−/− mice. Both inhibitors prevented lymphocyte apoptosis and improved survival. Caspase-3−/− mice shared a decreased, but not total, block of apoptosis. The polycaspase inhibitor caused a very substantial decrease in bacteremia. Caspase inhibitors did not benefit RAG-1−/− mice, which had a >tenfold increase in bacteremia compared to controls. Adoptive transfer of T cells that overexpressed the anti-apoptotic protein Bcl-2 increased survival. T cells stimulated with anti-CD3 and anti-CD28 produced increased interleukin 2 and interferon γ by 6 h. Thus, caspase inhibitors enhance immunity by preventing lymphocyte apoptosis and lymphocytes act rapidly, within 24 h, to control infection.
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We thank M. Laregina, Assistant Director, Diagnostic Services, Division of Comparative Medicine and the Barnes Jewish Hospital Microbiology Laboratory, Washington University School of Medicine for their help with the bacteriological studies. Supported by Merck Frosst (NIH GM44118 and GM 55194) and the Alan A. and Edith L. Wolff Foundation.
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Hotchkiss, R., Chang, K., Swanson, P. et al. Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1, 496–501 (2000). https://doi.org/10.1038/82741
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