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.

Insight into PreImplantation Factor (PIF*) Mechanism for Embryo Protection and Development: Target Oxidative Stress and Protein Misfolding (PDI and HSP) through Essential RIPK Binding Site

“…Proteomic analysis of the pancreas demonstrated that the ranking proteins which were up-regulated are the PDI and HSP family members. Further, both the neuroinflammation and GVHD models demonstrated that the highest ranking pathway/mechanism of PIF-induced protection was against oxidative stress and protein misfolding [27], [28], [30], [31], [44] [45], [46] [47]. Thus fundamental mechanisms through which PIF operates in the embryo are clearly translatable for non-pregnant immune disorder models.…”

PreImplantation Factor (PIF*) endogenously prevents preeclampsia: Promotes trophoblast invasion and reduces oxidative stress

“…These are in line with observations made in non-pregnant in vivo models. Specifically, in several models of immunity and transplant, PIF led to protection against oxidative stress (Weiss et al, 2011(Weiss et al, , 2012Azar et al, 2013;Shainer et al, 2013;Almogi-Hazan et al, 2014;Mueller et al, 2014Mueller et al, , 2015. In addition, as recently shown, PIF also protects against ionized radiation-induced damage (Shainer et al, 2014).…”

“…This folding structure has to be maintained to be biologically active since the scrambled PIF (same aminoacids but in random order) does not replicate PIF effect, bioinfromatics, in vitro ( Fig. 1) (Barnea et al, 2012b;, as well as in vivo (Weiss et al, 2011;Azar et al, 2013). Based on recent data PIF targets Kv1.3␤-cortisone target (Paidas et al, 2010;.…”

PreImplantation factor (PIF*) promotes embryotrophic and neuroprotective decidual genes: effect negated by epidermal growth factor

“…Additionally, the angiotensin family (1–7) increases neuronal voltage-gated potassium current through nitric oxide pathway [14,56]. Furthermore, viral infections cause, in the prenatal period, activation of the inOS pathway in murine models [57]. We demonstrated that PIF controls the inflammatory response in macrophages by blocking this specific pathway [58].…”