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

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.