Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response

Simone, Nicoletta Di; Nicuolo, Fiorella Di; Marana, Riccardo; Castellani, Roberta; Ria, Francesco; Veglia, Manuela; Scambia, Giovanni; Surbek, Daniel; Barnea, Eytan R.; Mueller, Martin

doi:10.1371/journal.pone.0180642

Cited by 24 publications

(40 citation statements)

References 70 publications

(106 reference statements)

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“…These are in vitro observations and therefore data using PIF in an in vivo setting would help to substantiate its potential clinical utility in treatment of pregnancy disorders. Recent data showed that in an immune intact murine model PIF administration reduces foetal death due to LPS administration [75]. Spontaneous pregnancy loss was also lowered.…”

Section: Discussionmentioning

confidence: 99%

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

Hakam

Miranda-Sayago

Hayrabedyan

et al. 2017

Cell Physiol Biochem

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Background/Aims: Pregnancy success requires mandatory maternal tolerance of the semi/ allogeneic embryo involving embryo-derived signals. Expression levels of PreImplantation Factor (PIF), a novel peptide secreted by viable embryos, correlate with embryo development, and its early detection in circulation correlates with a favourable pregnancy outcome. PIF enhances endometrial receptivity to promote embryo implantation. Via the p53 pathway, it increases trophoblast invasion, improving cell survival / immune privilege. PIF also reduces spontaneous and LPS-induced foetal death in immune naïve murine model. We examined PIF effect on gene expression of human leukocyte antigen (HLA-G, -E -F and –C) and the influence of PIF on local progesterone activity in JEG-3 choriocarcinoma cells. Methods: PIF and progesterone (P4) effects on JEG-3 cells surface and intracellular HLA molecules was tested using monoclonal antibodies, flow cytometry, and Western blotting. PIF and IL17 effects on P4 and cytokines secretion was determined by ELISA. PIF and P4 effects on JEG-3 cells proteome was examined using 2D gel staining followed by spot analysis, mass spectrometry and bioinformatic analysis. Results: In cytotrophoblastic JEG-3 cells PIF increased intracellular expression of HLA-G, HLA-F, HLA-E and HLA-C and surface expression of HLA-G, HLA-E and HLA-C in dose and time dependent manner. In case of HLA-E, -F results were confirmed also by Western blot. Proteome analysis confirmed an increase in HLA-G, pro-tolerance FOXP3+ regulatory T cells (Tregs), coagulation factors and complement regulator. In contrast, PIF reduced PRDX2 and HSP70s to negate oxidative stress and protein misfolding. PIF enhanced local progesterone activity, increasing steroid secretion and the receptor protein. It also promoted the secretion of the Th1/Th2 cytokines (IL-10, IL-1β, IL-8, GM-CSF and TGF-β1), resulting in improved maternal signalling. Conclusion: PIF can generate a pro-tolerance milieu by enhancing the expression of HLA molecules and by amplifying endogenous progesterone activity. A Fast-Track clinical trial for autoimmune disease has been satisfactorily completed. The acquired data warrants PIF use for the treatment of early pregnancy disorders.

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Section: Discussionmentioning

confidence: 99%

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

Hakam

Miranda-Sayago

Hayrabedyan

et al. 2017

Cell Physiol Biochem

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“…PIF shows local effects on the endometrium and trophoblast promoting implantation and invasion of the trophoblast and has a direct impact on immune cell function and targets neutrophils and macrophages, as well as CD4+ and CD8+ T-cells (109). PIF reduces the activation of the NALP3 inflammasome complex (mainly TLR-4 mediated) resulting in reduction of pro-inflammatory cytokines such as IL-1β, IL-18, and IL-33 (110,111). In addition, PIF creates an antiinflammatory milieu by reducing IFNγ and stimulating IL-10 secretion, as well as enhancing Th2 cytokines.…”

Section: Host-microbiota Interaction During Implantation and Placentamentioning

confidence: 99%

“…An exaggerated maternal immune response is putatively linked to preterm birth and fetal loss (172). Therefore, a novel strategy could be the maternal immune system modulation by synthetic PIF (110). Inflammatory challenge during pregnancy results in endogenous PIF expression and additional administration of synthetic PIF could prevent fetal loss.…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction

et al. 2020

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In the last decade, the microbiota, i.e., combined populations of microorganisms living inside and on the surface of the human body, has increasingly attracted attention of researchers in the medical field. Indeed, since the completion of the Human Microbiome Project, insight and interest in the role of microbiota in health and disease, also through study of its combined genomes, the microbiome, has been steadily expanding. One less explored field of microbiome research has been the female reproductive tract. Research mainly from the past decade suggests that microbial communities residing in the reproductive tract represent a large proportion of the female microbial network and appear to be involved in reproductive failure and pregnancy complications. Microbiome research is facing technological and methodological challenges, as detection techniques and analysis methods are far from being standardized. A further hurdle is understanding the complex host-microbiota interaction and the confounding effect of a multitude of constitutional and environmental factors. A key regulator of this interaction is the maternal immune system that, during the peri-conceptional stage and even more so during pregnancy, undergoes considerable modulation. This review aims to summarize the current literature on reproductive tract microbiota describing the composition of microbiota in different anatomical locations (vagina, cervix, endometrium, and placenta). We also discuss putative mechanisms of interaction between such microbial communities and various aspects of the immune system, with a focus on the characteristic immunological changes during normal pregnancy. Furthermore, we discuss how abnormal microbiota composition, "dysbiosis," is linked to a spectrum of clinical disorders related to the female reproductive system and how the maternal immune system is involved. Finally, based on the data presented in this review, the future perspectives in diagnostic approaches, research directions and therapeutic opportunities are explored.

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“…PIF is a 15‐amino acid polypeptide (MVRIKPGSANKPSDD) that is secreted by all viable (mammalian) embryos during intrauterine pregnancy . PIF acts to initiate and maintain intra‐uterine (local) tolerance, but also has effects on the systemic maternal immune response—possibly explaining the remission of autoimmune diseases while pregnant . PIF is effective at low concentrations (nanomolar) in the blood with a universal cross‐species (mammalian) effect .…”

Section: Preclinical Studiesmentioning

confidence: 99%

“…(14,15) PIF acts to initiate and maintain intra-uterine (local) tolerance, but also has effects on the systemic maternal immune response-possibly explaining the remission of autoimmune diseases while pregnant. (8,(16)(17)(18)(19)(20)(21)(22)(23) PIF is effective at low concentrations (nanomolar) in the blood with a universal cross-species (mammalian) effect. (24) We studied an exact analog of this native polypeptide, synthetic PIF (sPIF), which replicates native PIF action in both in vitro as well as in vivo preclinical studies.…”

mentioning

confidence: 99%

Randomized, Double‐Blind, Placebo‐Controlled, Single Ascending Dose Trial of Synthetic Preimplantation Factor in Autoimmune Hepatitis

O’Brien

Barnea²,

Martín

et al. 2018

Hepatology Communications

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Preimplantation factor (PIF) is an evolutionary conserved peptide secreted by viable embryos which promotes maternal tolerance without immune suppression. Synthetic PIF (sPIF) replicates native peptide activity. The aim of this study was to conduct the first‐in‐human trial of the safety, tolerability, and pharmacokinetics of sPIF in patients with autoimmune hepatitis (AIH). We performed a randomized, double‐blind, placebo‐controlled, prospective phase I clinical trial. Patients were adults with documented AIH with compensated chronic liver disease. Diagnosis of AIH was confirmed by either a pretreatment International Criteria for the Diagnosis of AIH score of 15 or more, or a posttreatment score of 17 or more. Patients were divided into three dosing cohorts (0.1, 0.5, or 1.0 mg/kg) of 6 patients in each group. Three patients in each group had normal liver tests and 3 patients had abnormal liver tests. They were randomized to receive a single, subcutaneous dose of either sPIF or a matching placebo. Eighteen patients were enrolled, and all successfully completed the trial. There were no clinically significant adverse events and all doses were well tolerated. Ascending doses of sPIF produced a linear increase in the respective serum levels with a half‐life of 90 minutes. There were no grade 2, 3 or 4 laboratory abnormalities. No patient developed detectable anti‐sPIF antibodies. Conclusion: This first‐in‐human trial of the safety and pharmacokinetics of sPIF (a novel biologic immune modulatory agent) demonstrated both excellent safety and tolerability. The data support further studies of multiple ascending doses of sPIF in autoimmune hepatitis and potentially other autoimmune disorders.

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Synthetic PreImplantation Factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response

Cited by 24 publications

References 70 publications

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

Preimplantation Factor (PIF) Promotes HLA-G, -E, -F, -C Expression in JEG-3 Choriocarcinoma Cells and Endogenous Progesterone Activity

The Interplay Between Reproductive Tract Microbiota and Immunological System in Human Reproduction

Randomized, Double‐Blind, Placebo‐Controlled, Single Ascending Dose Trial of Synthetic Preimplantation Factor in Autoimmune Hepatitis

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