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

An Erratum to this article was published on 12 April 2011


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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  1. 1.

    M.M. Lederman, J.J. Ellner, H.M. Rodman, J. Immunol. 127, 2051–2055 (1981)

    PubMed  CAS  Google Scholar 

  2. 2.

    M. Asano, M. Toda, N. Sakaguchi, S. Sakaguchi, J. Exp. Med. 184, 387–396 (1996)

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    B. Salomon, D.J. Lenschow, L. Rhee, N. Ashourian, B. Singh, A. Sharpe, J.A. Bluestone, Immunity 12, 431–440 (2000)

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    D. Bresson, M. von Herrath, Drug Discov. Today Dis. Mech. 1, 321–327 (2004)

    Article  CAS  Google Scholar 

  5. 5.

    J.J. Devoss, A.K. Shum, K.P. Johannes, W. Lu, A.K. Krawisz, P. Wang, T. Yang, N.P. Leclair, C. Austin, E.C. Strauss, M.S. Anderson, J. Immunol. 181, 4072–4079 (2008)

    PubMed  CAS  Google Scholar 

  6. 6.

    D. Pitocco, F. Zaccardi, E. Di Stasio, F. Romitelli, F. Martini, G.L. Scaglione, D. Speranza, S. Santini, C. Zuppi, G. Ghirlanda, Diabetes Res. Clin. Pract. 86(3), 173–176 (2009)

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    R.A. Ritzel, Front. Biosci. 14, 1835–1850 (2009). Review

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    K.C. Herold, W. Hagopian, J.A. Auger, E. Poumian-Ruiz, L. Taylor, D. Donaldson, S.E. Gitelman, D.M. Harlan, D. Xu, R.A. Zivin, J.A. Bluestone, N. Engl. J. Med. 346, 1692–1698 (2002)

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    G.S. Eisenbarth, S. Srikanta, R. Jackson, S. Rabinowe, R. Dolinar, T. Aoki, M.A. Morris, Diabetes Res. 2, 271–276 (1985)

    PubMed  CAS  Google Scholar 

  10. 10.

    I. Raz, D. Elias, A. Avron, M. Tamir, M. Metzger, I.R. Cohen, Lancet 358, 1749–1753 (2001)

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    M. Bitan, L. Weiss, M. Zeira, S. Reich, O. Pappo, S. Vlodavsky, S. Slavin, Diabetes Metab. Res. Rev. 24, 413–421 (2008)

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    L. Weiss, S. Slavin, S. Reich, P. Cohen, S. Shuster, R. Stern, E. Kaganovsky, E. Okon, A.M. Rubinstein, D. Naor, Proc. Natl. Acad. Sci. USA 97, 285–290 (2000)

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    G. Elkin, T.B. Prigozhina, S. Slavin, Prevention of TIDM in nonobese diabetic mice by non myeloablative allogenic bone marrow transplantation. Exp. Hematol. 32, 579–584 (2004)

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    M. Koulmanda, E. Budo, S. Bonner-Weir, A. Qipo, P. Putheti, N. Degauque, H. Shi, Z. Fan, J.S. Flier, H. Auchincloss Jr., X.X. Zheng, T.B. Strom, Proc. Natl. Acad. Sci. USA 104, 13074–13079 (2007)

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    B. Runmarker, O. Andersen, Brain 188, 253–261 (1995)

    Article  Google Scholar 

  16. 16.

    A. Doria, L. Iaccarino, S. Arienti, A. Ghirardello, S. Zampieri, M.E. Rampudda, S. Cutolo, A. Tincani, S. Todesco, Reprod. Toxicol. 2, 234–241 (2006). Review

    Article  Google Scholar 

  17. 17.

    C. Huang, F. Snider, J.C. Cross, Endocrinology. 150, 1618–1626 (2009). Epub 2008 Nov 26

    Google Scholar 

  18. 18.

    M. Ostensen, F. Forger, BMJ 328, 915 (2004)

    Article  Google Scholar 

  19. 19.

    E. R. Barnea, R. Perez, P. C. Leavis, Assays for preimplantation factor and preimplantation factor peptides. USPTO 7,273,708 B2. September 2007

  20. 20.

    E.R. Barnea, J. Simon, S.P. Levine, C.B. Coulam, G.S. Taliadouros, P.C. Leavis, Am. J. Reprod. Immunol. 42, 95–99 (1999)

    PubMed  CAS  Google Scholar 

  21. 21.

    E.R. Barnea, Am. J. Reprod. Immunol. 51, 319–322 (2004)

    PubMed  Article  Google Scholar 

  22. 22.

    E.R. Barnea, Ann. N. Y. Acad. Sci. 1110, 602–618 (2007)

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    E.R. Barnea, S. Sharma, Prediction of implantation in ART using molecular biology, in Contemporary Perspectives on Assisted Reproductive Technology, ed. by G.N. Allahbadia, R. Merchant (Reed Elsevier, India, 2007), pp. 183–194

    Google Scholar 

  24. 24.

    E. R. Barnea, in Signaling Between Embryo and Mother in Early Pregnancy: Basis for Development of Tolerance. ed. by H. Carp. Recurrent Pregnancy Loss (Taylor & Francis, London) pp. 15–22

  25. 25.

    E. R. Barnea, D. Kirk, PIF modulated gene expression in human Peripheral Blood Mononuclear Cell (PBMC) (Homo sapiens GSE18291 [Accession]) (2009),

  26. 26.

    M. J. Paidas, G. Krikun, J. Huang, R. Jones, M. Romano, J. Annunziato, E. R. Barnea, Am. J. Obstet. Gynecol. 202, 459.e1–459.e8 (2010)

    Google Scholar 

  27. 27.

    C. Duzyj, E. R. Barnea, M. Li, S. J. Huang, G. Krikun, M. J. Paidas, Am J Obstet Gynecol, 203, 402.e1–402.e4 (2010). Epub 2010 Aug 12

    Google Scholar 

  28. 28.

    M. Jurewicz, S. Yang, A. Augello, J. G. Godwin, R. F. Moore, J. Azzi, P. Fiorina, M. Atkinson, M. H. Sayegh, R. Abdi, Diabetes (2010). Sept 2010 Ahead of print

  29. 29.

    R. Geoffrey, S. Jia, A.E. Kwitek, J. Woodliff, S. Ghosh, A. Lernmark, X. Wang, M.J. Hessner, J. Immunol. 177, 7275–7286 (2006)

    PubMed  CAS  Google Scholar 

  30. 30.

    A.D. Recklies, C. White, H. Ling, Biochem. J. 365, 119–126 (2002)

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    B. Zhong, P. Strand, D.M. Toivola, G.Z. Tao, X. Ji, H.B. Greenberg, M.B. Omary, Mol. Biol. Cell 18, 4969–4978 (2007)

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    L.G. Xu, M. Wu, J. Hu, Z. Zhai, H.B. Shu, J. Leukoc. Biol. 72, 410–416 (2002)

    PubMed  CAS  Google Scholar 

  33. 33.

    J. M. Fernández-Real, F. Equitani, J. M. Moreno, M. Manco, F. Ortega, W. Ricart. J. Clin. Endocrinol. Metab. (2008) Dec 30. [Epub ahead of print]

  34. 34.

    I.C. Gerling, S. Sudhir, N.I. Lenchik, D.R. Marshall, J. Wu, Mol. Cell. Proteomics 5, 293–306 (2006)

    PubMed  CAS  Google Scholar 

  35. 35.

    K.S. Na, B.C. Park, M. Jang, S. Cho, H. do Lee, S. Kang, C.K. Lee, K.H. Bae, S.G. Park, Mol Cells 24, 261–267 (2007)

    PubMed  CAS  Google Scholar 

  36. 36.

    S.S. Solomon, N. Buss, J. Shull, S. Monnier, G. Majumdar, J. Wu, C. Gerling, J. Lab. Clin. Med. 145, 275–283 (2005)

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    D.C. Thurmond, C. Gonelle-Gispert, M. Furukawa, P.A. Halban, J.E. Pessin, Mol. Endocrinol. 17, 732–742 (2003)

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Y.W. Chang, J.A. Traugh, M. Li, Mol. Cell. Biol. 28, 4549–4561 (2008)

    Article  Google Scholar 

  39. 39.

    R.R. Ramos, A.J. Swanson, J. Bass, Proc. Natl. Acad. Sci. 104, 10470–10475 (2007)

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    P. Yang, M. Li, D. Guo, F. Gong, B.L. Adam, M.A. Atkinson, C.Y. Wang, Ann. N. Y. Acad. Sci. 1150, 68–71 (2008)

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    R.M. Szmola, C. Sahin-Tóth, Proc. Natl. Acad. Sci. 104, 11227–11232 (2007)

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    T.M. Hansner, M. Kauer, G. Gornitzka, H. Kolb, S. Martin, Exp. Clin. Endocrinol. Diab. 112, 288–293 (2004)

    Article  CAS  Google Scholar 

  43. 43.

    A. E.Handel, L. Handunethi, G. C. Ebers, S. V. Ramagopalan, Nat Rev Endocrinol. 5(12), 655–664 (2009). Epub 2009 Nov

    Google Scholar 

  44. 44.

    B. H. Choi, S. J. Hahn, Acta Pharmacol. Sin (2010) 31, 1031–1035

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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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Correspondence to Eytan R. Barnea.

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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 (2011).

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  • TIDM
  • Preimplantation factor
  • Therapy
  • Pancreas
  • NOD