High‐density lipoprotein infusion protects from acute graft‐versus‐host disease in experimental allogeneic hematopoietic cell transplantation

Acute graft‐versus‐host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram‐negative bacteria are well‐known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in...

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Bibliographic Details
Published in:American journal of transplantation 2022-05, Vol.22 (5), p.1350-1361
Main Authors: Chagué, Cécile, Gautier, Thomas, Dal Zuffo, Ludivine, Pais de Barros, Jean‐Paul, Wetzel, Audrey, Tarris, Georges, Pallot, Gaëtan, Martin, Laurent, Valmary‐Degano, Séverine, Deckert, Valérie, Lagrost, Laurent, Daguindau, Etienne, Saas, Philippe
Format: Article
Language:English
Subjects:
Acute Disease
Animal models
Animals
Bone marrow
bone marrow/hematopoietic stem cell transplantation
CD8 antigen
CD8-Positive T-Lymphocytes
Cholangitis
Graft vs Host Disease - etiology
Graft vs Host Disease - prevention & control
graft‐versus‐host disease (GVHD)
Gram-negative bacteria
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cell Transplantation - methods
High density lipoprotein
Immune clearance
immune regulation
Immunomodulation
Interferon
Lipopolysaccharides
Lipopolysaccharides - metabolism
Lipoproteins, HDL - metabolism
Liver
liver disease: immune/inflammatory
Liver diseases
Lymphocytes T
Macrophages
Mice
Original
ORIGINAL ARTICLES
Stem cell transplantation
translational research/science
Transplantation
Transplantation, Homologous
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Summary:Acute graft‐versus‐host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram‐negative bacteria are well‐known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein‐mediated transport to the liver (i.e., the so‐called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL‐deficient (Apoa1tm1Unc) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon‐γ‐secreting CD8+ T cells and non‐resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL‐based therapies in the prevention of aGVHD. In a mouse model of acute graft‐versus‐host disease, high density lipoprotein infusions reduce mortality and disease severity by reducing both systemic and local inflammation.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.16960