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Journal of Assisted Reproduction and Genetics

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01-01-2018 | Fertility Preservation

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

Authors: Michael Feichtinger, Eytan R. Barnea, Atunga Nyachieo, Mats Brännström, S. Samuel Kim

Published in: Journal of Assisted Reproduction and Genetics | Issue 1/2018

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.

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.PubMedCrossRef

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.PubMedCrossRef

Scott JR, Hendrickson M, Lash S, Shelby J. Pregnancy after tubo-ovarian transplantation. Obstet Gynecol. 1987;70(2):229–34.PubMed

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.PubMedCrossRef

Kim SS, Battaglia DE, Soules MR. The future of human ovarian cryopreservation and transplantation: fertility and beyond. Fertil Steril. 2001;75(6):1049–56.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.CrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentral

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

55.

Stevens VC. Some reproductive studies in the baboon. Hum Reprod Update. 1997;3(6):533–40.PubMedCrossRef

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.

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.PubMedCrossRef

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.CrossRef

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 50-1PubMed

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.PubMedCrossRef

61.

Robertson JA. Ethical issues in ovarian transplantation and donation. Fertil Steril. 2000;73(3):443–6.PubMedCrossRef

Title: Allogeneic ovarian transplantation using immunomodulator preimplantation factor (PIF) as monotherapy restored ovarian function in olive baboon
Authors: Michael Feichtinger
Eytan R. Barnea
Atunga Nyachieo
Mats Brännström
S. Samuel Kim
Publication date: 01-01-2018
Publisher: Springer US
Published in: Journal of Assisted Reproduction and Genetics / Issue 1/2018
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-017-1051-y

At a glance: The STEP trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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