Prevention of GVHD by a probiotic exopolysaccharide.

摘要 移植物抗宿主病（GVHD）是异基因造血干细胞移植后常见的致死性并发症 用于治疗多种恶性血液病的移植。GVHD的结果来自于对 宿主细胞通过供体的同种异体反应性T细胞。GVHD的标准预防和治疗是给药 广泛的免疫抑制药物，抑制同种异体反应性T细胞。然而，这些治疗作为一种 副作用增加感染风险尽管有预防和治疗药物，但约50%的 这些患者发展为急性GVHD，其中许多人继续发展为慢性GVHD，导致 高死亡率。一旦建立，cGVHD很难治疗。 我们从一种土壤细菌枯草芽孢杆菌中鉴定出一种胞外多糖（EPS） 诱导抗炎骨髓细胞，抑制T细胞的激活。我们有数据显示， EPS抑制同种异体鼠细胞培养物中的混合淋巴细胞反应（MLR），以及同种异体 人体细胞此外，EPS施用抑制接受同种异体移植物的小鼠中GVHD的发展。 造血干细胞移植该补助金的第一年的目标是确定EPS是否可以成为一部小说 用于改善人类GVHD的药物。为了测试这一点，我们将使用“人源化”NGS-HLA-A2小鼠，其中 重建表达人HLA-A2 MHC I类分子的免疫缺陷NGS-HLA-A2小鼠 人外周血单核细胞。这种植入将导致由于供体的活化而引起的allo-GVHD。 通过受体的同种异体HLA-A2分子，以及由于供体T细胞的活化而引起的异种GVHD， 异种鼠分子的影响该模型已被证明是人类GVHD的优秀模型。 在我们的实验中，我们将首先检查以确定hPBMC在EPS处理的NGS-LHA-A2中移植 小鼠，并确定EPS的最大耐受剂量（目标1）。在目标2中，我们会向受助人发放易办事， 确定GVHD的临床症状是否受到抑制，在目标3中，我们将测试EPS是否影响移植物与 白血病（GvL）效应。如果EPS抑制GVHD，但不显著 影响GvL效应或造血细胞的重建，我们将得出结论，EPS可能是一种新的药物， GVHD的预防和治疗。

Abstract Graft versus host disease (GVHD) is an often lethal complication from allogeneic hematopoietic stem cell transplantation used as treatment for a variety of hematologic malignancies. GVHD results from an attack on host cells by alloreactive T cells of the donor. Standard prevention and treatment for GVHD is administration of broadly immunosuppressive drugs, which suppress alloreactive T cells. These treatments however, have as a side-effect, increased risk for infection. Despite the drugs available for prevention and treatment, ~50% of these patients develop acute GVHD, and many of these continue on to develop chronic GVHD, which results in high mortality. Once established, cGVHD is difficult to treat. We have identified a molecule, exopolysaccharide (EPS) from a commensal soil bacterium, Bacillus subtilis that induces anti-inflammatory myeloid cells, which inhibit activation of T cells. We have data showing that EPS inhibits mixed lymphocyte reactions (MLR) in cultures of allogeneic murine cells, as well as allogeneic human cells. Further, EPS administration inhibits development of GVHD in mice receiving allogeneic hematopoietic stem cell transplants. The goal of the first year of this grant is to determine if EPS can be a novel drug used to ameliorate GVHD in humans. To test this, we will use “humanized” NGS-HLA-A2 mice, in which the immunodeficient NGS-HLA-A2 mice expressing human HLA-A2 MHC class I molecules, are reconstituted with human peripheral blood monocytes. Such engraftment will result in allo-GVHD due to activation of donor T cells by allogeneic HLA-A2 molecules of the recipient, and also xeno-GVHD due to activation of donor T cells by xenogeneic murine molecules. This model has been shown to serve as an excellent model for human GVHD. In our experiments, we will first check to establish that hPBMCs are engrafted in EPS-treated NGS-LHA-A2 mice and determine maximal tolerated dose of EPS (Aim 1). In Aim 2, we will administer EPS to recipients and determine if the clinical symptoms of GVHD are inhibited, and in Aim 3, we will test if EPS affects the graft vs leukemia (GvL) effect resulting from allo-transplantation. If EPS inhibits GVHD, but does not significantly affect the GvL effect or reconstitution of hematopoietic cells, we will conclude that EPS is likely a novel drug for prevention and treatment of GVHD.