Project description:To identify systemic cytokine patterns in Chronic Graft-versus-Host-Disease (CGVHD), we profiled the gene expression of circulating monocytes. Pathway analysis identified two gene sets that were significantly upregulated across a broad range of patients with inflammatory and sclerotic presentations: (1) genes induced by Type I and Type II IFN, and (2) receptor genes for innate immune responses to cellular damage. Multiple IFN-inducible genes involved in signal transduction, anti-viral function, lymphocyte homeostasis, trafficking, and antigen presentation were increased. Furthermore, upregulation of TLR/NLR/CLR receptor genes for nucleic acids, ribonucleoproteins and annexin implicated response to damaged cells as a source of activation of inflammasomes and induction of Type I IFN. Serial time courses substantiated a pattern of upregulation of multiple IFN-inducible genes at CGVHD onset, and of decline upon therapy and resolution. Corticosteroid effects could be discriminated from CGVHD gene profiles by assessment of glucocorticoid-inducible genes. Elevated expression of IFN-inducible proteins in plasma and tissue substantiated a role for IFN in lymphocyte trafficking and, through upregulation of BAFF, an involvement of IFN in B cell activation in CGVHD. These results support a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.
Project description:RATIONALE: Beclomethasone may be an effective treatment for graft-versus-host disease.
PURPOSE: Phase I/II trial to study the effectiveness of beclomethasone in treating patients who have graft-versus-host disease of the esophagus, stomach, small intestine, or colon.
Project description:This phase II trial studies how well cyclophosphamide works in preventing chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplant in patients with hematological malignancies. Giving chemotherapy and total-body irradiation before transplantation helps stop the growth of cancer cells and prevents the patient’s immune system from rejecting the donor’s stem cells. Healthy stem cells from a donor that are infused into the patient help the patient’s bone marrow make blood cells; red blood cells, white blood cells, and platelets. Sometimes, however, the transplanted donor cells can cause an immune response against the body’s normal cells, which is called graft-versus-host disease (GVHD). Giving cyclophosphamide after transplant may prevent this from happening or may make chronic GVHD less severe.
Project description:To assess the preclinical utility and functional mechanism of intraperitoneal anti-CX3CL1 mAb therapy in the skin and lung fibrosis, sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) model mice were analyzed by RNA-sequencing assays.
Project description:Allogeneic hematopoietic stem cell transplantation remains the most efficacious treatment for many hematological malignancies. However, its therapeutic potential is affected by the most prominent side effect graft versus host disease. Despite advances in the treatment of graft versus host disease in recent years, morbidity and mortality remains high, which requires the development of new treatment approaches. We therefore implemented mouse models to assess potential treatment options for graft versus host disease. In in vivo experiments, we had observed a protective effect of LCN2 on graft versus host disease of the gastrointestinal tract. We also observed higher numbers of anti-inflammatory macrophages in the intestinal tissues of these animals. Therefore, we aimed to determine potentially regulated genes in these cells by using an in vitro approach of LCN2-treated macrophages.
