Amelioration of Graft-versus-Host Disease by Exopolysaccharide from a Commensal Bacterium

Abstract

Acute graft-versus-host disease (aGvHD) is a severe, often lethal, complication of hematopoietic stem cell transplantation, and although prophylactic regimens are given as standard pretransplantation therapy, up to 60% of these patients develop aGvHD, and require additional immunosuppressive intervention. We treated mice with a purified probiotic molecule, exopolysaccharide (EPS) from Bacillus subtilis, shortly before and after induction of aGvHD and found that, whereas only 10% of control mice survived to day 80, 70% of EPS-treated mice survived to 80 d. EPS treatment of donor-only mice resulted in ∼60% survival. Using a biosensor mouse model to assess inflammation in live mice during aGvHD, we found that EPS prevented the activation of alloreactive donor T cells. In vitro, EPS did not affect T cells directly but, instead, induced bone marrow–derived dendritic cells (BMDCs) that displayed characteristics of inhibitory dendritic cells (DCs). Development of these BMDCs required TLR4 signaling through both MyD88 and TRIF pathways. Using BMDCs derived from IDO knockout mice, we showed that T cell inhibition by EPS-treated BMDCs was mediated through the suppressive effects of IDO. These studies describe a bacterial molecule that modulates immune responses by inducing inhibitory DCs in a TLR4-dependent manner, and these cells have the capacity to inhibit T cell activation through IDO. We suggest that EPS or EPS-treated DCs can serve as novel agents for preventing aGvHD.

Characterization of age-associated inflammasome activation reveals tissue specific differences in transcriptional and post-translational inflammatory responses

“…To characterize global changes in inflammasome activation during aging, we used caspase-1 reporter mice described previously to visualize caspase-1 activation in vivo and ex vivo (37, 40, 41, 43). At ∼18 months of age, mice exhibited increased biosensor activation in vivo ( Fig 1A-B ), consistent with age-dependent increase in low-grade systemic inflammation.…”

“…To characterize global and tissue-specific changes in inflammasome activation during the process of aging, we utilized a transgenic mouse model in which a luciferase-based caspase-1 biosensor is constitively expressed in all tissues (37). Proteolytic activation of caspase-1 thus induces luciferase activation in specific tissues, allowing inflammasome activation to be monitored in vivo and ex vivo (37)(38)(39)(40)(41)(42)(43). These studies reveal a tissue-specific degree of overlap or discordance between age-associated inflammasome activation and upregulation of inflammatory transcripts commonly associated with inflammaging.…”

Inflammasome activation occurs in CD4+ and CD8+ T cells during graft-versus-host disease

“…Caspase-1 is active in allogeneic CD4 + and CD8 + T cells in mice with aGvHD A number of groups have observed irradiation-induced inflammasome/inflammatory caspase activation in recipient tissues in mice [15][16][17] and in patients with severe GvHD [15], although there has been little investigation into the contribution of inflammatory caspase activation in alloreactive T cells, the cells driving pathology in this disease. Our previous data suggested that inflammatory caspases were active in allogeneic splenocytes [10,11]. To interrogate this further, we used the C57Bl/6 (H-2Kb) → BALB/c (H-2Kd) MHC major mismatched model of aGvHD (Fig.…”

“…However, many of these studies fail to account for the existence of numerous inflammasome receptors, many of which are poorly characterized, as well as the redundant roles of caspases as inflammasome effectors. Our previous results suggested that inflammatory caspase activation occurs in donor splenocytes in a model of aGvHD [ 10 , 11 ]. Here, we demonstrate activation of caspase-1 in alloreactive T cells using mouse and human models of aGvHD.…”

Nutritional modulation of the gut microbiome in allogeneic hematopoietic stem cell transplantation recipients

“…In mouse models, the administration of exopolysaccharide derived from Bacillus subtilis ameliorated aGvHD improving GvHD related mortality. This effect was mediated by the induction of inhibitory dentritic cells in a TLR4-dependent manner (105). SCFAs are the most investigated, and they represent a effector route in common with prebiotic compounds.…”