To clarify the role of gur mucosal immunity in ASD, we evaluated, in the early-life immune activation (BIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (as mab), blocking the leukocyte homing into the gut mucosa. BIA is a double-hit variant of the maternal immune-activation (MLA) model, including both prenatal (Foly I:C) and postnatal (LFS) immune challenges. In C57BL6J BIA male adult offspring mice, IL-1ss and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4 a407, unstimulated and stimulated IL- 17A and stimulated IPM- lymphocytes in MLN and CD4 a4j7 unetimulated and stimulated IL-17A and stimulated IFN- lymphocytes in the spleen. Treatment with anti-3487 mab in BIA male mice was associated with colonic tissue IL-18 and IL-17A mRNA content and percentage of CD4 IL-17A and IFN-y+ lymphocytes in MLN and spleens comparable to control mice. The anti-0487 mb treatment rescue social novelty deficit showed in the three-chamber test by BIA male mice. Increased levels of IL-6 and IL-10 and decreased CD68 and TOP- mRNAs were also observed in hippocampus and prefrontal cortex of BIA male mice together with a reduction of BDNF MRNA levels in all brain regions examined. Anti-0417 mab treatment restored the expression of BDNP. TGF-B and CD68 in hippocampus and prefrontal cortes Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first pre- clinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (4171) lymphocytes expressing IL-17A
Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder / Butera, Alessia; De Simone, Roberta; Potenza, Rosa Luisa; Sanchez, Massimo; Armida, Monica; Campanile, Doriana; Di Carlo, Nazzareno; Trenta, Francesco; Boirivant, Monica; Ricceri, Laura. - In: BRAIN, BEHAVIOR, AND IMMUNITY. - ISSN 1090-2139. - 115:(2024). [10.1016/j.bbi.2023.09.024]
Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder
Butera, Alessia;Trenta, Francesco;Boirivant, Monica;
2024
Abstract
To clarify the role of gur mucosal immunity in ASD, we evaluated, in the early-life immune activation (BIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (as mab), blocking the leukocyte homing into the gut mucosa. BIA is a double-hit variant of the maternal immune-activation (MLA) model, including both prenatal (Foly I:C) and postnatal (LFS) immune challenges. In C57BL6J BIA male adult offspring mice, IL-1ss and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4 a407, unstimulated and stimulated IL- 17A and stimulated IPM- lymphocytes in MLN and CD4 a4j7 unetimulated and stimulated IL-17A and stimulated IFN- lymphocytes in the spleen. Treatment with anti-3487 mab in BIA male mice was associated with colonic tissue IL-18 and IL-17A mRNA content and percentage of CD4 IL-17A and IFN-y+ lymphocytes in MLN and spleens comparable to control mice. The anti-0487 mb treatment rescue social novelty deficit showed in the three-chamber test by BIA male mice. Increased levels of IL-6 and IL-10 and decreased CD68 and TOP- mRNAs were also observed in hippocampus and prefrontal cortex of BIA male mice together with a reduction of BDNF MRNA levels in all brain regions examined. Anti-0417 mab treatment restored the expression of BDNP. TGF-B and CD68 in hippocampus and prefrontal cortes Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first pre- clinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (4171) lymphocytes expressing IL-17AI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
