title: Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model).
abstract: Bone marrow transplantation (BMT) to treat severe hematologic malignancies often leads to potentially fatal acute graft-versus-host disease (GVHD), despite attempts at better donor-recipient matching and/or use of immunosuppressive agents. We report that embryo-derived PreImplantation Factor (PIF) plays a determining role in developing maternal/host tolerance toward the semiallogeneic or total allogeneic embryo and in regulating systemic immune response. Synthetic PIF treatment has proven effective in preventing immune attacks in nonpregnant models of autoimmunity. In this study, we tested the capability of PIF to prevent the development of acute GVHD in semiallogeneic or totally allogeneic murine BMT models. We examined the regulatory effect of PIF both in vivo and in vitro to control deleterious GVHD while maintaining its ability to preserve the beneficial graft-versus-leukemia (GVL) effect. Bone marrow and spleen cells from C57BL/6 donors were transplanted in semiallogeneic (C57BL/6xBALB/c) F1 or allogeneic (BALB/c) mice, which were then treated with PIF 1 mg/kg/day for 2 weeks. Short-term PIF administration reduced acute GVHD in both models and increased survival for up to 4 months after semiallogeneic or totally allogeneic BMT. This effect was coupled with decreased skin inflammation (semiallogeneic model) and decreased liver inflammation (both models), as well as reduced colon ulceration (allogeneic model). GVHD-associated cytokine and chemokine gene expression were decreased in the liver. PIF further lowered circulating IL-17 levels, but not IFN-γ levels. Both in vivo and in vitro, PIF treatment was demonstrated to lead to decreased inducible nitric oxide synthase expression and decreased lipopolysaccharide-activated macrophages to lower nitric oxide secretion. Significantly, PIF did not diminish the beneficial GVL effect in the B cell leukemia model. PIF acts primarily by inducing the regulatory phenotype on monocytes/antigen-presenting cells, which controls T cell proliferation. Overall, our data demonstrate that PIF protects against semiallogeneic and allogeneic GVHD long term by reducing both target organ and systemic inflammation and by decreasing oxidative stress, while preserving the beneficial GVL effect.
authors.affiliation: Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Yehudith
authors.initials: Y
authors.lastname: Azar
authors.forename: Reut
authors.initials: R
authors.lastname: Shainer
authors.forename: Osnat
authors.initials: O
authors.lastname: Almogi-Hazan
authors.forename: Rachel
authors.initials: R
authors.lastname: Bringer
authors.forename: Susan R
authors.initials: SR
authors.lastname: Compton
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Paidas
authors.forename: Eytan R
authors.initials: ER
authors.lastname: Barnea
authors.forename: Reuven
authors.initials: R
authors.lastname: Or
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17; D010455:Peptides; C569738:preimplantation factor, synthetic; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse