Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 1, pp 81–89 | Cite as

Allogeneic ovarian transplantation using immunomodulator preimplantation factor (PIF) as monotherapy restored ovarian function in olive baboon

  • Michael Feichtinger
  • Eytan R. Barnea
  • Atunga Nyachieo
  • Mats Brännström
  • S. Samuel Kim
Fertility Preservation

Abstract

Purpose

Allogeneic ovarian transplantation may be an alternative in the future to oocyte donation in women with premature ovarian failure. The objectives of this study were to (a) evaluate allotransplantation feasibility for restoration of ovarian function and (b) assess efficacy of synthetic preimplantation factor (PIF) monotherapy as sole immune-acceptance regimen.

Methods

This is an experimental animal study using non-human primates (Papio anubis). Allogeneic orthotopic ovarian tissue transplantation was performed in two female olive baboons. PIF was administered as a monotherapy to prevent immune rejection and achieve transplant maintenance and function. Subjects underwent bilateral oophorectomy followed by cross-transplantation of prepared ovarian cortex. Postoperatively, subjects were monitored for clinical and biochemical signs of graft rejection and return of function. Weekly blood samples were obtained to monitor graft acceptance and endocrine function restoration.

Results

Postoperatively, there were no clinical signs of rejection. Laboratory parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine) did not indicate organ rejection at any stage of the experiment. Initially, significant loss of follicles was noticed after grafting and serum follicle-stimulating hormone (FSH) and E2 levels were consistent with ovarian failure. Seven months after transplantation, one animal exhibited recurrence of ovarian endocrine function (perineal swelling, E2 rise, FSH decrease, and return of menstruation).

Conclusions

Organ rejection after allogeneic ovarian transplantation was prevented using PIF as monotherapy for the first time and no side effects were recorded. The study suggests the clinical feasibility of ovarian allotransplantation to obtain ovarian function.

Keywords

PIF Ovarian graft Fertility preservation Ovary Transplantation Preimplantation factor Allotransplantation POF Premature ovarian failure Premature ovarian insufficiency POI Baboon 

Notes

Acknowledgements

The present study was presented at the late-breaking abstract session of the ASRM annual meeting in Salt-Lake City, October 19th 2016. The authors wish to thank Ms. Sharon Chepkwony and Mr. Nicholas Kiulia for their organizational help at the Institute of Primate Research (IPR), Karen, Kenya, and Dr. David Erikson for hormonal assays at the Oregon National Primate Research Center, OR, Portland. In addition, we appreciate Amy Carter and Stephanie Zinn for editorial assistance.

Funding

This study was funded by the Medical Scientific Fund of the Mayor of Vienna (Nr.:14063), the Wunschbaby Institut Feichtinger, by an unrestricted grant from BioIncept and by private funds of M.F. and S.S.K.

Compliance with ethical standards

The study was approved by the Institutional Animal Care and Use Committee (IACUC) of the Institute of Primate Research (IPR), Karen, Kenya (Ref.: IRC/10/14).

References

  1. 1.
    Kim SS. Fertility preservation in female cancer patients: current developments and future directions. Fertil Steril. 2006;85(1):1–11.  https://doi.org/10.1016/j.fertnstert.2005.04.071.PubMedCrossRefGoogle Scholar
  2. 2.
    Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364(9443):1405–10.  https://doi.org/10.1016/S0140-6736(04)17222-X.PubMedCrossRefGoogle Scholar
  3. 3.
    Scott JR, Hendrickson M, Lash S, Shelby J. Pregnancy after tubo-ovarian transplantation. Obstet Gynecol. 1987;70(2):229–34.PubMedGoogle Scholar
  4. 4.
    Carmona F, Balasch J, Gonzalez-Merlo J. Ovarian function, tubal viability and pregnancy after tubo-ovarian transplantation in the rabbit. Hum Reprod. 1993;8(6):929–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Kim SS, Battaglia DE, Soules MR. The future of human ovarian cryopreservation and transplantation: fertility and beyond. Fertil Steril. 2001;75(6):1049–56.PubMedCrossRefGoogle Scholar
  6. 6.
    Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet. 1999;353(9158):1083–91.  https://doi.org/10.1016/S0140-6736(98)07493-5.PubMedCrossRefGoogle Scholar
  7. 7.
    Mhatre P, Mhatre J. Orthotopic ovarian transplant—review and three surgical techniques. Pediatr Transplant. 2006;10(7):782–7.  https://doi.org/10.1111/j.1399-3046.2006.00547.x.PubMedCrossRefGoogle Scholar
  8. 8.
    Mhatre P, Mhatre J, Magotra R. Ovarian transplant: a new frontier. Transplant Proc. 2005;37(2):1396–8.  https://doi.org/10.1016/j.transproceed.2004.11.083.PubMedCrossRefGoogle Scholar
  9. 9.
    Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7(3):241–6.  https://doi.org/10.1038/ni1317.PubMedCrossRefGoogle Scholar
  10. 10.
    Barnea ER. Insight into early pregnancy events: the emerging role of the embryo. Am J Reprod Immunol. 2004;51(5):319–22.  https://doi.org/10.1111/j.1600-0897.2004.00159.x.PubMedCrossRefGoogle Scholar
  11. 11.
    Barnea ER. Applying embryo-derived immune tolerance to the treatment of immune disorders. Ann N Y Acad Sci. 2007;1110:602–18.  https://doi.org/10.1196/annals.1423.064.PubMedCrossRefGoogle Scholar
  12. 12.
    Barnea ER. Signaling between embryo and mother in early pregnancy: basis for development of tolerance. In: Carp HJA, editor. Recurrent pregnancy loss—causes, controversies, and treatment. Second ed. Boca Raton: CRC Press; 2014. p. 17–28.Google Scholar
  13. 13.
    Barnea ER, Rambaldi M, Paidas MJ, Mecacci F. Reproduction and autoimmune disease: important translational implications from embryo-maternal interaction. Immunotherapy. 2013;5(7):769–80.  https://doi.org/10.2217/imt.13.59.PubMedCrossRefGoogle Scholar
  14. 14.
    Stamatkin CW, Roussev RG, Stout M, Absalon-Medina V, Ramu S, Goodman C, et al. Preimplantation factor (PIF) correlates with early mammalian embryo development-bovine and murine models. Reproductive biology and endocrinology : RB&E. 2011;9:63.  https://doi.org/10.1186/1477-7827-9-63.CrossRefGoogle Scholar
  15. 15.
    Stamatkin CW, Roussev RG, Stout M, Coulam CB, Triche E, Godke RA, et al. Preimplantation factor negates embryo toxicity and promotes embryo development in culture. Reprod BioMed Online. 2011;23(4):517–24.  https://doi.org/10.1016/j.rbmo.2011.06.009.PubMedCrossRefGoogle Scholar
  16. 16.
    Barnea ER, Hayrabedyan S, Todorova K, Almogi-Hazan O, Or R, Guingab J, et al. Preimplantation factor (PIF*) regulates systemic immunity and targets protective regulatory and cytoskeleton proteins. Immunobiology. 2016;221(7):778–93.  https://doi.org/10.1016/j.imbio.2016.02.004.PubMedCrossRefGoogle Scholar
  17. 17.
    Chen YC, Rivera J, Fitzgerald M, Hausding C, Ying YL, Wang X, et al. Preimplantation factor prevents atherosclerosis via its immunomodulatory effects without affecting serum lipids. Thromb Haemost. 2016;115(5):1010–24.  https://doi.org/10.1160/TH15-08-0640.PubMedCrossRefGoogle Scholar
  18. 18.
    Weiss L, Bernstein S, Jones R, Amunugama R, Krizman D, Jebailey L, et al. Preimplantation factor (PIF) analog prevents type I diabetes mellitus (TIDM) development by preserving pancreatic function in NOD mice. Endocrine. 2011;40(1):41–54.  https://doi.org/10.1007/s12020-011-9438-5.PubMedCrossRefGoogle Scholar
  19. 19.
    Weiss L, Or R, Jones RC, Amunugama R, JeBailey L, Ramu S, et al. Preimplantation factor (PIF*) reverses neuroinflammation while promoting neural repair in EAE model. J Neurol Sci. 2012;312(1–2):146–57.  https://doi.org/10.1016/j.jns.2011.07.050.PubMedCrossRefGoogle Scholar
  20. 20.
    Mueller M, Schoeberlein A, Zhou J, Joerger-Messerli M, Oppliger B, Reinhart U, et al. Preimplantation factor bolsters neuroprotection via modulating protein kinase A and protein kinase C signaling. Cell Death Differ. 2015;22(12):2078–86.  https://doi.org/10.1038/cdd.2015.55.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Mueller M, Zhou J, Yang L, Gao Y, Wu F, Schoeberlein A, et al. Preimplantation factor promotes neuroprotection by targeting microRNA let-7. Proc Natl Acad Sci U S A. 2014;111(38):13882–7.  https://doi.org/10.1073/pnas.1411674111.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Shainer R, Almogi-Hazan O, Berger A, Hinden L, Mueller M, Brodie C, et al. Preimplantation factor (PIF) therapy provides comprehensive protection against radiation induced pathologies. Oncotarget. 2016;7(37):58975–94.  10.18632/oncotarget.10635.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Azar Y, Shainer R, Almogi-Hazan O, Bringer R, Compton SR, Paidas MJ, et al. Preimplantation factor reduces graft-versus-host disease by regulating immune response and lowering oxidative stress (murine model). Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2013;19(4):519–28.  https://doi.org/10.1016/j.bbmt.2012.12.011.CrossRefGoogle Scholar
  24. 24.
    Shainer R, Azar Y, Almogi-Hazan O, Bringer R, Compton SR, Paidas MJ, et al. Immune regulation and oxidative stress reduction by preimplantation factor following syngeneic or allogeneic bone marrow transplantation. Conference Papers in Medicine. 2013;2013(Article ID 718031):1–8.  https://doi.org/10.1155/2013/718031.CrossRefGoogle Scholar
  25. 25.
    Barnea ER, Almogi-Hazan O, Or R, Mueller M, Ria F, Weiss L, et al. Immune regulatory and neuroprotective properties of preimplantation factor: from newborn to adult. Pharmacol Ther. 2015;156:10–25.  https://doi.org/10.1016/j.pharmthera.2015.10.008.PubMedCrossRefGoogle Scholar
  26. 26.
    Johannesson L, Enskog A, Molne J, Diaz-Garcia C, Hanafy A, Dahm-Kahler P, et al. Preclinical report on allogeneic uterus transplantation in non-human primates. Hum Reprod. 2013;28(1):189–98.  https://doi.org/10.1093/humrep/des381.PubMedCrossRefGoogle Scholar
  27. 27.
    Enskog A, Johannesson L, Chai DC, Dahm-Kahler P, Marcickiewicz J, Nyachieo A, et al. Uterus transplantation in the baboon: methodology and long-term function after auto-transplantation. Hum Reprod. 2010;25(8):1980–7.  https://doi.org/10.1093/humrep/deq109.PubMedCrossRefGoogle Scholar
  28. 28.
    Di Simone N, Di Nicuolo F, Marana R, Castellani R, Ria F, Veglia M, et al. Synthetic preimplantation factor (PIF) prevents fetal loss by modulating LPS induced inflammatory response. PLoS One. 2017;12(7):e0180642.  https://doi.org/10.1371/journal.pone.0180642.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Migliara G, Mueller M, Piermattei A, Brodie C, Paidas MJ, Barnea ER, et al. PIF* promotes brain re-myelination locally while regulating systemic inflammation- clinically relevant multiple sclerosis M.smegmatis model. Oncotarget. 2017;8(13):21834–51.  10.18632/oncotarget.15662.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Jensen JT, Zelinski MB, Stanley JE, Fanton JW, Stouffer RL. The phosphodiesterase 3 inhibitor ORG 9935 inhibits oocyte maturation in the naturally selected dominant follicle in rhesus macaques. Contraception. 2008;77(4):303–7.  https://doi.org/10.1016/j.contraception.2008.01.003.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Varlamov O, White AE, Carroll JM, Bethea CL, Reddy A, Slayden O, et al. Androgen effects on adipose tissue architecture and function in nonhuman primates. Endocrinology. 2012;153(7):3100–10.  https://doi.org/10.1210/en.2011-2111.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Bauer C. The baboon (Papio sp.) as a model for female reproduction studies. Contraception. 2015;92(2):120–3.  https://doi.org/10.1016/j.contraception.2015.06.007.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet. 2015;32(8):1167–70.  https://doi.org/10.1007/s10815-015-0544-9.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Brannstrom M, Johannesson L, Bokstrom H, Kvarnstrom N, Molne J, Dahm-Kahler P, et al. Livebirth after uterus transplantation. Lancet. 2015;385(9968):607–16.  https://doi.org/10.1016/S0140-6736(14)61728-1.PubMedCrossRefGoogle Scholar
  35. 35.
    Johannesson L, Kvarnstrom N, Molne J, Dahm-Kahler P, Enskog A, Diaz-Garcia C, et al. Uterus transplantation trial: 1-year outcome. Fertil Steril. 2015;103(1):199–204.  https://doi.org/10.1016/j.fertnstert.2014.09.024.PubMedCrossRefGoogle Scholar
  36. 36.
    Yin H, Wang X, Kim SS, Chen H, Tan SL, Gosden RG. Transplantation of intact rat gonads using vascular anastomosis: effects of cryopreservation, ischaemia and genotype. Hum Reprod. 2003;18(6):1165–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Gosden RG. Survival of ovarian allografts in an experimental animal model. Pediatr Transplant. 2007;11(6):628–33.  https://doi.org/10.1111/j.1399-3046.2007.00715.x.PubMedCrossRefGoogle Scholar
  38. 38.
    Meraz MM, Juarez CG, Monsalve CR, Martinez-Chequer JC, Duvignau JM, Fernandez EM, et al. Restoration of endocrine function and fertility with orthotopic tubal-ovarian allotransplant as the anatomical-functional unit in rabbits. Journal of investigative surgery : the official journal of the Academy of Surgical Research. 2008;21(6):348–59.  https://doi.org/10.1080/08941930802438930.CrossRefGoogle Scholar
  39. 39.
    Lin YH, Yeh YC, Tzeng CR, Shang WJ, Liu JY, Chen CH. Evaluating the effects of immunosuppression by in-vivo bioluminescence imaging after allotransplantation of ovarian grafts. Reprod BioMed Online. 2011;22(2):220–7.  https://doi.org/10.1016/j.rbmo.2010.10.010.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen CH, Yeh YC, Wu GJ, Huang YH, Lai WF, Liu JY, et al. Tracking the rejection and survival of mouse ovarian iso- and allografts in vivo with bioluminescent imaging. Reproduction. 2010;140(1):105–12.  https://doi.org/10.1530/REP-09-0448.PubMedCrossRefGoogle Scholar
  41. 41.
    Maclaran K, Panay N. Premature ovarian failure. The journal of family planning and reproductive health care. 2011;37(1):35–42.  https://doi.org/10.1136/jfprhc.2010.0015.PubMedCrossRefGoogle Scholar
  42. 42.
    van der Schouw YT, van der Graaf Y, Steyerberg EW, Eijkemans JC, Banga JD. Age at menopause as a risk factor for cardiovascular mortality. Lancet. 1996;347(9003):714–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Rocca WA, Grossardt BR, de Andrade M, Malkasian GD, Melton LJ 3rd. Survival patterns after oophorectomy in premenopausal women: a population-based cohort study. The Lancet Oncology. 2006;7(10):821–8.  https://doi.org/10.1016/S1470-2045(06)70869-5.PubMedCrossRefGoogle Scholar
  44. 44.
    Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, et al. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009;94(7):2277–83.  https://doi.org/10.1210/jc.2008-1878.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Schmidt PJ, Luff JA, Haq NA, Vanderhoof VH, Koziol DE, Calis KA, et al. Depression in women with spontaneous 46, XX primary ovarian insufficiency. J Clin Endocrinol Metab. 2011;96(2):E278–87.  https://doi.org/10.1210/jc.2010-0613.PubMedCrossRefGoogle Scholar
  46. 46.
    van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999;5(5):483–92.PubMedCrossRefGoogle Scholar
  47. 47.
    Asch R, Balmaceda J, Ord T, Borrero C, Cefalu E, Gastaldi C, et al. Oocyte donation and gamete intrafallopian transfer as treatment for premature ovarian failure. Lancet. 1987;1(8534):687.PubMedCrossRefGoogle Scholar
  48. 48.
    Vujovic S, Brincat M, Erel T, Gambacciani M, Lambrinoudaki I, Moen MH, et al. EMAS position statement: managing women with premature ovarian failure. Maturitas. 2010;67(1):91–3.  https://doi.org/10.1016/j.maturitas.2010.04.011.PubMedCrossRefGoogle Scholar
  49. 49.
    Moindjie H, Santos ED, Loeuillet L, Gronier H, de Mazancourt P, Barnea ER, et al. Preimplantation factor (PIF) promotes human trophoblast invasion. Biol Reprod. 2014;91(5):118.  https://doi.org/10.1095/biolreprod.114.119156.PubMedCrossRefGoogle Scholar
  50. 50.
    Barnea ER, Simon J, Levine SP, Coulam CB, Taliadouros GS, Leavis PC. Progress in characterization of pre-implantation factor in embryo cultures and in vivo. Am J Reprod Immunol. 1999;42(2):95–9.PubMedGoogle Scholar
  51. 51.
    Roussev RG, Dons'koi BV, Stamatkin C, Ramu S, Chernyshov VP, Coulam CB, et al. Preimplantation factor inhibits circulating natural killer cell cytotoxicity and reduces CD69 expression: implications for recurrent pregnancy loss therapy. Reprod BioMed Online. 2013;26(1):79–87.  https://doi.org/10.1016/j.rbmo.2012.09.017.PubMedCrossRefGoogle Scholar
  52. 52.
    Lopez-Cabrera M, Santis AG, Fernandez-Ruiz E, Blacher R, Esch F, Sanchez-Mateos P, et al. Molecular cloning, expression, and chromosomal localization of the human earliest lymphocyte activation antigen AIM/CD69, a new member of the C-type animal lectin superfamily of signal-transmitting receptors. J Exp Med. 1993;178(2):537–47.PubMedCrossRefGoogle Scholar
  53. 53.
    Schowengerdt KO, Fricker FJ, Bahjat KS, Kuntz ST. Increased expression of the lymphocyte early activation marker CD69 in peripheral blood correlates with histologic evidence of cardiac allograft rejection. Transplantation. 2000;69(10):2102–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Posselt AM, Vincenti F, Bedolli M, Lantz M, Roberts JP, Hirose R. CD69 expression on peripheral CD8 T cells correlates with acute rejection in renal transplant recipients. Transplantation. 2003;76(1):190–5.  https://doi.org/10.1097/01.TP.0000073614.29680.A8.PubMedCrossRefGoogle Scholar
  55. 55.
    Stevens VC. Some reproductive studies in the baboon. Hum Reprod Update. 1997;3(6):533–40.PubMedCrossRefGoogle Scholar
  56. 56.
    D’Hooghe T, Mwenda JM, Hill JA. The baboon as a nonhuman primate model for the study of human reproduction. Gynecol Obstet Invest. 2004;57:1–60.Google Scholar
  57. 57.
    Amorim CA, Jacobs S, Devireddy RV, Van Langendonckt A, Vanacker J, Jaeger J, et al. Successful vitrification and autografting of baboon (Papio anubis) ovarian tissue. Hum Reprod. 2013;28(8):2146–56.  https://doi.org/10.1093/humrep/det103.PubMedCrossRefGoogle Scholar
  58. 58.
    Nyachieo A, Spiessens C, Chai DC, Kiulia NM, Willemen D, Mwenda JM, et al. Ovarian tissue cryopreservation by vitrification in olive baboons (Papio anubis): a pilot study. Gynecol Obstet Investig. 2013;75(3):157–62.  https://doi.org/10.1159/000346084.CrossRefGoogle Scholar
  59. 59.
    Todo S, Demetris A, Ueda Y, Imventarza O, Cadoff E, Zeevi A, et al. Renal transplantation in baboons under FK 506. Surgery. 1989;106(2):444–50. discussion 50-1PubMedGoogle Scholar
  60. 60.
    Kim SS, Yang HW, Kang HG, Lee HH, Lee HC, Ko DS, et al. Quantitative assessment of ischemic tissue damage in ovarian cortical tissue with or without antioxidant (ascorbic acid) treatment. Fertil Steril. 2004;82(3):679–85.  https://doi.org/10.1016/j.fertnstert.2004.05.022.PubMedCrossRefGoogle Scholar
  61. 61.
    Robertson JA. Ethical issues in ovarian transplantation and donation. Fertil Steril. 2000;73(3):443–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Michael Feichtinger
    • 1
    • 2
  • Eytan R. Barnea
    • 3
    • 4
  • Atunga Nyachieo
    • 5
  • Mats Brännström
    • 6
    • 7
  • S. Samuel Kim
    • 8
    • 9
  1. 1.Department of Obstetrics and Gynecology, Division of Gynecologic Endocrinology and Reproductive MedicineMedical University of ViennaViennaAustria
  2. 2.Wunschbaby Institut FeichtingerViennaAustria
  3. 3.BioIncept, LLCCherry HillUSA
  4. 4.SIEP, Society for the Investigation of Early PregnancyCherry HillUSA
  5. 5.Institute of Primate ResearchKarenKenya
  6. 6.Department of Obstetrics and GynecologyUniversity of GothenburgGothenburgSweden
  7. 7.Stockholm IVFStockholmSweden
  8. 8.University of KansasKansas CityUSA
  9. 9.American-Sino Women’s and Children’s HospitalShanghaiChina

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