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.
Public Health Relevance Statement: Project Narrative. 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. Despite drugs for prevention and treatment of GVHD, ~50% of these transplant patients develop acute or chronic GVHD, often leading to high mortality. We propose to use a novel molecule, EPS from a commensal soil bacterium to inhibit activation of alloreactive T cells and prevent development of GVHD. Experiments are proposed with humanized mice to test if EPS can prevent GVHD caused by alloreactive T cells.
Project Terms: Acute; Acute Graft Versus Host Disease; Affect; Allogenic; Animal Model; Animals; Anti-Inflammatory Agents; Antigens; B-Lymphocytes; Bacillus subtilis; Bacteria; base; bioluminescence imaging; Bone Marrow; Cells; cellular engineering; Chronic; chronic graft versus host disease; Clinical; Complication; cytokine; Data; Dendritic Cells; Development; Disease; Dose; Drug usage; Engineering; Engraftment; experimental study; Goals; graft vs host disease; graft vs leukemia effect; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; HLA-A2 Antigen; Human; humanized mouse; Immune; Immunity; Immunologics; improved; In Vitro; in vivo; infection risk; Inflammatory; Inflammatory Response; Intervention; Legal patent; Letters; Leukemic Cell; Licensing; Luciferases; macrophage; Massachusetts; Maximum Tolerated Dose; Mediating; MHC antigen; Mixed Lymphocyte Culture Test; Modeling; monocyte; mortality; mouse model; Mus; Myeloid Cells; Natural Killer Cells; novel; novel therapeutics; Organ; Pathology; Patients; peripheral blood; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; prevent; Prevention; Probiotics; Proliferating; prophylactic; reconstitution; Regimen; response; Serum; Severity of illness; side effect; Soil; Spleen; Symptoms; System; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Therapeutic Agents; Tissues; Transplant Recipients; Transplantation; Universities; Xenograft procedure
