Modulation of bacterial endotoxin-induced tolerance / immunosuppression

REARTE B.; MAGLIOCO A; BRUZZO J; LANDONI V.I; FERNÁNDEZ G C; RUGGIERO R.A; ISTURIZ M.A.

Congreso; First French - Argentine Immunology Congress, LVIII Reunión Anual de la Sociedad Argentina de Inmunología, XIII Jornada Científica del Grupo Rioplatense de Citometría de Flujo, 3º Jornadas Argentinas de Inmunodeficiencias Primarias (SAP); 2010

Sociedad Argentina de Inmunología, French Society of Immunology

Endotoxin tolerance, defined as a reduced responsiveness to lipopolysaccharides (LPS) after a first encounter with endotoxin, could be involved in sepsis-associated immunosuppression. Previously we demonstrated that RU486, a glucocorticoid-receptor antagonist, induces the disruption of tolerance in mice. The aim of this study was to evaluate the effect of RU486 on both the secondary humoral and cellular immune response in LPS-induced immunosuppresed/tolerant mice (IS). In addition, we evaluated the presence of regulatory/suppressor cells, myeloid-derived GR1+CD11b+ suppressor (MDSC) and regulatory T cells (Treg) and their involvement in the tolerance phenomenon. BALB/c mice immunized with sheep red blood cells were then treated with LPS (IS). Then, mice were immunized again and treated with RU486. Antibodies production was evaluated by hemagglutination on day 7. To evaluate cellular response, IS were treated with RU486 and inoculated with radiated tumor cells and then were challenged with live tumor cells. Tumor presence was observed 10 days later. To elucidate the role of cells in the LPS tolerance maintenance we used cyclophosphamide (C) and gemcitabine (G) that reduces the number of both populations. Treatment with RU486 partially restored both the humoral response (IS: 93±5 vs ISRU486: 225±35; mean ±SEM hemagglutination titre; p<0.01) and cellular immune response (tumor growth = IS: 10/11; ISRU486: 3/12; p<0.01) in IS mice. Cell number reduction of Treg as well MDSC did not disrupt the LPS tolerance maintenance since all groups survived against a lethal dose of LPS: (MDSC: IS 1x108±0.6x107 vs ISG 0.2x108±1x107, p<0.001; Treg: IS 1x107±8x105 vs ISC 0.2x107±1x105, p<0.001). RU486 partially restores the humoral and cellular immune response in IS, suggesting the involvement of endogenous glucocorticoids (GC). The regulatory/ suppressor cells do not play a major role in the LPS tolerance phenomenon and their presence seems to be a peripheral phenomenon of GC action.