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Maladie du greffon contre l'hôte aigüe (GVHa) : impact des lipopolysaccharides circulants et place du métabolisme des lipoprotéines pour leur neutralisation

Abstract : Acute Graft-versus-Host Disease (aGVHD) remains an important cause of mortality and morbidity after allogeneic hematopoietic cell transplantation (AHCT). Lipopolysaccharides (LPS) are described as critical triggers of antigen-presenting cell (APC) priming, cytokine release and intestinal mucosal damage sustainment. We hypothesize that modulating the reverse LPS transport (RLT) is a potential approach to mitigate aGVHD through the disruption of the inflammatory cascade initiated by LPS signaling. The RLT is a counterpart of reverse cholesterol transport in which lipophilic substances are integrated into high-density lipoproteins (HDL) for liver clearance.Using validated AHCT mouse models, we have confirmed the systemic LPS exposure by an innovative technique based on high performance liquid chromatography coupled to mass spectrometry and investigated the role of RLT by modulating several effectors or potential regulators. Our major findings show that:i)In the complete absence of circulating HDL (i.e. in ApoA1tm1Unc knock-out mice), recipient mice experienced a more severe GVHD associated with an increased APC maturation and type 1 T cell responses in the spleen and the liver.ii)The level of circulating HDL is collapsed in GVHD mice but could be corrected by repeated intravenous infusion of HDL isolated from human plasma. The restoration of HDL pool leads to an increased survival and a decreased GVHD severity. Furthermore, HDL infusion reduces the concentration of circulating and biliary LPS, the capacity of splenocytes to sustain alloreactive responses and the production of pro-inflammatory cytokines by liver APC (namely, Küpffer cells and non-resident macrophages).Taken together, these results suggest that HDL infusion may be a potential prophylactic approach for aGVHD.
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https://tel.archives-ouvertes.fr/tel-03201807
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Submitted on : Monday, April 19, 2021 - 12:26:08 PM
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Cécile Chagué. Maladie du greffon contre l'hôte aigüe (GVHa) : impact des lipopolysaccharides circulants et place du métabolisme des lipoprotéines pour leur neutralisation. Médecine humaine et pathologie. Université Bourgogne Franche-Comté, 2019. Français. ⟨NNT : 2019UBFCE022⟩. ⟨tel-03201807⟩

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