Effects of All-Trans-retinoic acid on the inmunosuppression associated to infectious processes in a murine model

MARTIRE-GRECO D; LANDONI V.I; CHIARELLA P; SCHIERLOH P.; REARTE B.; ISTURIZ M.A.; FERNANDEZ G.C.

Bs As

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

Immunosuppresssion related to late phases of sepsis is a medical concern associated with high mortality rates. The model of tolerance to LPS mimics several aspects of sepsis-associated immunosuppression. In this sense an increase of myeloid-derived suppressor cells (MDSC, Gr-1+CD11b+CD31+) has been related to the derangements observed in the immune response. All-trans-retinoic acid (ATRA) is a derivative of vitamin-A with immunomodulating properties, that eliminates MDSC, inducing their differentiation. Our hypothesis is that ATRA could restore the immunological competence in the model of tolerance to LPS. We investigated the effects of ATRA on different immune parameters. Increasing i.p. doses of LPS were administered for 20 days and orally doses of ATRA were given for the last 13 days (LPS: 5 to 20 µg/day/mouse, ATRA: 500 µg/day/mouse). Using flow cytometry we observed that ATRA decreased the percentage (%) of MDSC in the spleen (LPS=1.67±0.17, LPS+ATRA=0.97±0.03, p<0.05), and increased the % of dendritic cells (CD11c+) in lymph nodes (LPS=1.9±0.1, LPS+ATRA=3.4±0.4, p<0.05). This was associated with an enhanced primary humoral immune response against a particulated T-dependent antigen measured by hemagglutination (Titre: LPS=2133±426, LPS+ATRA=6827±1707, p<0.05). Whereas LPS increased the anti-inflammatory cytokine IL-10 in plasma, ATRA reversed this effect (pg/ml: LPS=181.6±84, LPS+ATRA=13.5±1.2, p<0.05). Additionally, in the site of LPS inoculation an influx of neutrophils (Gr-1+ F4/80-) was observed in LPS-treated mice, concomitantly with a loss of macrophages (F4/80+); ATRA increased the macrophage population, and decreased neutrophils (%Gr-1+ F4/80-: LPS=58.9±1.1, LPS+ATRA=27.6±0.2, p<0.05; %F4/80+: LPS=2.1±0.8, LPS+ATRA=6.3±0.1, p<0.05). ATRA decreased local inflammation and reversed several parameters associated with the immunosuppression observed in the state of tolerance to LPS, and may be involve in the restoration of the immunological competence.