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Preimplantation factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice

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An Erratum to this article was published on 12 April 2011

Abstract

Preimplantation factor (PIF) is a novel embryo-secreted immunomodulatory peptide. Its synthetic analog (sPIF) modulates maternal immunity without suppression. There is an urgent need to develop agents that could prevent the development of type 1 diabetes mellitus (TIDM). Herein, we examine sPIF’s preventive effect on TIDM development by using acute adoptive-transfer (ATDM) and spontaneously developing (SDM) in non-obese diabetic (NOD) murine models. Diabetes was evaluated by urinary and plasma glucose, intraperitoneal glucose tolerance test (IPGTT), pancreatic islets insulin staining by immunohistochemistry and by pancreatic proteome evaluation using mass spectrometry, followed by signal pathway analysis. Continuous administration of sPIF for 4-weeks prevents diabetes development in ATDM model in >90% of recipients demonstrated by normal IPGTT, preserved islets architecture, number, and insulin staining. (P < 0.01). sPIF effect was specific; its protective effects are not replicated by scrambled PIF (χ2 = 0.009) control. sPIF led also to increased circulating Th2 and Th1 cytokines. In SDM model, 4-week continuous sPIF administration prevented onset of diabetes for 21 weeks post-therapy (P < 0.01). Low-dose sPIF administration for 16 weeks prevented diabetes development up to 14 weeks post-therapy, evidenced by preserved islets architecture and insulin staining. In SDM model, pancreatic proteome pathway analysis demonstrated that sPIF regulates protein traffic, prevents protein misfolding and aggregation, and reduces oxidative stress and islets apoptosis, leading to preserved insulin staining. sPIF further increased insulin receptor expression and reduced actin and tubulin proteins, thereby blocking neutrophil invasion and inflammation. Exocrine pancreatic function was also preserved. sPIF administration results in marked prevention of spontaneous and induced adoptive-transfer diabetes suggesting its potential effectiveness in treating early-stage TIDM.

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Acknowledgments

We thank Professor Naor, Hebrew U, Jerusalem, Israel, for donating NOD mice. We thank Kay Jenkins for analyzing the mice pancreas by IHC. sPIF is a proprietary compound (BioIncept LLC).

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Authors and Affiliations

  1. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Hadassah University Hospital Ein Kerem, Hebrew University, Jerusalem, Israel

    Lola Weiss, Osnat Hazan, Janna Yachtin, Reut Shiner, Israel Reibstein & Reuven Or

  2. QualTek Molecular Laboratories, Santa Barbara, CA, USA

    Steve Bernstein

  3. NextGen Sciences Ltd., Ann Arbor, MI, USA

    Richard Jones & Ravi Amunugama

  4. Expression Pathology, Inc., Gaithersburg, MD, USA

    David Krizman

  5. GeneGo Inc., St. Joseph, MI, USA

    Lellean JeBailey

  6. International Center for Cell Therapy & Cancer Immunotherapy (CTCI), Tel Aviv, Israel

    Shimon Slavin

  7. Department of Community Health and Epidemiology, Brown University School of Medicine, Providence, RI, USA

    Elizabeth Triche

  8. The Society for the Investigation of Early Pregnancy (SIEP), 1697 Lark Lane, Cherry Hill, NJ, 08003, USA

    Eytan R. Barnea

  9. Department of Obstetrics and Gynecology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, NJ, USA

    Eytan R. Barnea

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  1. Lola Weiss
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Correspondence to Eytan R. Barnea.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s12020-011-9464-3

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Weiss, L., Bernstein, S., Jones, R. et al. Preimplantation factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice. Endocrine 40, 41–54 (2011). https://doi.org/10.1007/s12020-011-9438-5

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