Prevention of GVHD by a probiotic exopolysaccharide.

通过益生菌胞外多糖预防 GVHD。

• 批准号: 10081555
• 负责人: Katherine L. Knight
• 金额: $ 30万
• 依托单位: HASENTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-07 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081555
• 关键词: Acute; Acute Graft Versus Host Disease; Affect; Allogenic; Animal Model; Animals; Anti-Inflammatory Agents; Antigens; B-Lymphocytes; Bacillus subtilis; Bacteria; Bone Marrow; Cells; Chronic; Clinical; Complication; Data; Dendritic Cells; Development; Disease; Dose; Drug usage; Engineering; Engraftment; Goals; Grant; HLA-A2 Antigen; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Human; Immune; Immunity; Immunologics; In Vitro; Inflammatory; Inflammatory Response; Intervention; Legal patent; Letters; Leukemic Cell; Licensing; Luciferases; MHC antigen; Massachusetts; Maximum Tolerated Dose; Mediating; Mixed Lymphocyte Culture Test; Modeling; Mus; Myeloid Cells; Natural Killer Cells; Organ; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Prevention; Probiotics; Proliferating; Regimen; Serum; Severity of illness; Soil; Spleen; Symptoms; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic Agents; Tissues; Transplant Recipients; Transplantation; Universities; Xenograft procedure; base; bioluminescence imaging; cellular engineering; chronic graft versus host disease; cytokine; experimental study; graft vs host disease; graft vs leukemia effect; humanized mouse; improved; in vivo; infection risk; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; peripheral blood; prevent; prophylactic; reconstitution; response; side effect

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.

抽象的 移植物抗宿主病（GVHD）是同种异体造血干细胞引起的一种常见致命并发症 移植用于治疗多种血液系统恶性肿瘤。 GVHD 是由攻击引起的 宿主细胞由供体的同种异体反应性 T 细胞产生。 GVHD 的标准预防和治疗是给药 广泛的免疫抑制药物，可抑制同种反应性 T 细胞。然而，这些治疗方法作为 副作用，增加感染风险。尽管有可用于预防和治疗的药物，但约 50% 这些患者出现急性 GVHD，其中许多人继续出现慢性 GVHD，从而导致 高死亡率。一旦形成，cGVHD 就很难治疗。 我们从共生土壤细菌枯草芽孢杆菌中鉴定出一种分子，胞外多糖 (EPS) 诱导抗炎骨髓细胞，从而抑制 T 细胞的激活。我们有数据表明 EPS 抑制同种异体小鼠细胞培养物以及同种异体细胞培养物中的混合淋巴细胞反应 (MLR) 人体细胞。此外，EPS 给药可抑制接受同种异体药物的小鼠发生 GVHD 造血干细胞移植。这笔赠款第一年的目标是确定 EPS 是否可以成为一种新颖的 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 重组表达人类 HLA-A2 MHC I 类分子的免疫缺陷 NGS-HLA-A2 小鼠 与人外周血单核细胞。由于供体的激活，这种植入将导致同种异体 GVHD 由受者的同种异体 HLA-A2 分子产生的 T 细胞，以及由于供体 T 细胞的激活而产生的异种 GVHD 由异种小鼠分子。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 是否已植入 EPS 处理的 NGS-LHA-A2 中 小鼠并确定 EPS 的最大耐受剂量（目标 1）。在目标 2 中，我们将向接收者管理 EPS，并 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 同种异体移植引起的白血病（GvL）效应。如果 EPS 抑制 GVHD，但不显着 影响 GvL 效应或造血细胞的重建，我们将得出结论，EPS 可能是一种新药 GVHD 的预防和治疗。