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; 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 移植与宿主疾病（GVHD）是同种异体造血干细胞的致命并发症 移植用作各种血液学恶性肿瘤的治疗方法。 GVHD是由对 宿主细胞通过供体的同种异体T细胞。 GVHD的标准预防和治疗是给药 广泛的免疫抑制药物，可抑制同种异体T细胞。但是，这些治疗方法是 副作用，感染风险增加。尽管有可预防和治疗的药物，但约有50％ 这些患者会出现急性GVHD，其中许多继续发展为慢性GVHD，这导致 高死亡率。一旦建立，CGVHD就很难治疗。 我们已经确定了来自共生土壤细菌的分子，外多糖（EPS） 这会诱导抗炎髓样细胞，从而抑制T细胞的激活。我们有数据显示 EPS抑制同种异体细胞培养物中的混合淋巴细胞反应（MLR）以及同种异体 人类细胞。此外，EPS给药抑制了接受同种异体的小鼠中GVHD的发展 造血干细胞移植。这笔赠款第一年的目标是确定EPS是否可以是新颖的 用于改善人类GVHD的药物。为了测试这一点，我们将使用“人性化” NGS-HLA-A2小鼠，其中 表达人HLA-A2 MHC I类的免疫缺陷NGS-HLA-A2小鼠是重组的 与人类外周血单核细胞。由于供体的激活，这种植入将导致Allo-GVHD T细胞由受体的同种异体HLA-A2分子，以及由于供体T细胞的激活而引起的Xeno-GVHD 通过异构鼠分子。该模型已被证明是人类GVHD的出色模型。 在我们的实验中，我们将首先检查以确定HPBMC植入了EPS处理的NGS-LHA-A2中 小鼠并确定EPS的最大耐受剂量（AIM 1）。在AIM 2中，我们将对接收者管理EPS和 确定GVHD的临床症状是否受到抑制，在AIM 3中，我们将测试EPS是否影响移植物与 白血病（GVL）效应是由异晶植入术引起的。如果EPS抑制GVHD，但没有显着 影响造血细胞的GVL效应或重构，我们将包括EPS可能是一种新颖的药物 GVHD的预防和处理。