Reproductive Sciences

, Volume 19, Issue 2, pp 123–134 | Cite as

Immunology of Uterine Transplantation: A Review

  • Srdjan Saso
  • Sadaf Ghaem-Maghami
  • Jayanta Chatterjee
  • Nancy Brewig
  • Laszlo Ungar
  • J. Richard Smith
  • Giuseppe Del PrioreEmail author


The idea of using organ transplantation to solve quality-of-life issues was first introduced a century ago, with cornea transplants and thrusted before the world again in 1998, following a controversial hand transplant. Uterus transplantation (UTn) has been proposed as another quality-of-life transplant for the cure of permanent uterine factor infertility. In order to proceed in humans, a greater appreciation of the immunological mechanisms that underlie UTn is desirable. Allogeneic UTn (animal model) was first described by 2 studies in 1969. The first and only human UTn, performed in 2000, was an early attempt with limited use of animal model experiments prior to moving onto the human setting. Since then, work using rat, mouse, ovine, goat, and nonhuman primate models has demonstrated that the uterus is a very different but manageable organ immunologically compared to other transplanted organs. Therefore, specifically exploring immunological issues relating to UTn is a valuable and necessary part of the inevitable scientific process leading to successful human UTn.


solid-organ transplantation uterus immunology fertility 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Nair A, Stega J, Smith JR, Del Priore G. Uterus Transplant. Evidence and Ethics. Ann NY Acad Sci. 2008;1127:83–91.Google Scholar
  2. 2.
    Keith Louis G, Del Priore G. Uterine transplantation in humans: a new frontier. Int J Gynecol Obstet. 2002; 76(3):243–244.Google Scholar
  3. 3.
    Altchek A. Uterus transplantation. Mount Sinai J Med. 2003;70: 154–162.Google Scholar
  4. 4.
    Smith JR, Boyle DCM, Corless DJ, et al. Abdominal trachelectomy. A new surgical technique for the conservative management of cervical carcinoma. Br J Obstet Gynaecol. 1997;104: 1196–1200.Google Scholar
  5. 5.
    Fageeh W, Raffa H, Jabbad H, Marzouki A. Transplantation of the human uterus. Int J Gynaecol Obstet. 2002;76(3):245–251.Google Scholar
  6. 6.
    Brannstrom M, Racho El-Akouri R, Wranning CA. Uterine transplantation. Eur J Obstet Gynecol Reprod Biol. 2003;109(2): 121–123.Google Scholar
  7. 7.
    Milliez J. Uterine transplantation: FIGO committee for the ethical aspects of human reproduction and women’’s health. Int J Gynaecol Obstet. 2009;106(3):270.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Salguero PC. The Buddhist medicine king in literary context: reconsidering an early medieval example of Indian influence on Chinese medicine and surgery. Hist Religions. 2009;48(3): 183–210.CrossRefGoogle Scholar
  9. 9.
    Nankivell BJ, Alexander SI. Rejection of the kidney allograft. N Engl J Med. 2010; 363(15):1451–1462.Google Scholar
  10. 10.
    Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol. 2007; 18(4):1046–1056.Google Scholar
  11. 11.
    Issa F, Schiopu A, Wood KJ. Role of T cells in graft rejection and transplantation tolerance. Expert Rev Clin Immunol. 2010;6(1): 155–169.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Briscoe DM, Alexander SI, Lichtman AH. Interactions between T lymphocytes and endothelial cells in allograft rejection. Curr Opin Immunol. 1998;10(5):525–531.Google Scholar
  13. 13.
    Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol. 2001;166(2): 973–981.Google Scholar
  14. 14.
    Csencsits KL, Bishop DK. Contrasting alloreactive CD4+ and CD8+ T cells: there’s more to it than MHC restriction. Am J Transplant. 2003;3(2):107–115.Google Scholar
  15. 15.
    Barry M, Bleackley RC. Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol. 2002;2(6):401–409.Google Scholar
  16. 16.
    Truta E, Pop I, Popa D, Ionescu M, Truta F. Experimental re- and transplantation of the internal female genital organs. Rom Med Rev. 1969;13(1):53–58.Google Scholar
  17. 17.
    Yonemoto RH, Du Sold WD, Deliman RM. Homotransplantation of uterus and ovaries in dogs. A preliminary report. Am J Obstet Gynecol. 1969;104(8):1143–1151.Google Scholar
  18. 18.
    Wingate MB, Karasewich E, Wingate L, Lauchian S, Ray M. Experimental uterotubovarian homotransplantation in the dog. Am J Obstet Gynecol. 1970;106(8):1171–1176.Google Scholar
  19. 19.
    Scott JR, Andersson WR, Kling TG, Yannone ME. Uterine transplantation in dogs. Gynecol Invest. 1970;1(3):140–148.Google Scholar
  20. 20.
    Scott JR, Pitkin RM, Yannone ME. Transplantation of the primate uterus. Surg Gynecol Obstet. 1971;133(3):414–418.Google Scholar
  21. 21.
    Confino E, Vermesh M, Thomas W Jr, Gleicher N. Non-vascular transplantation of the rabbit uterus. Int J Gynaecol Obstet. 1986; 24(4):321–325.Google Scholar
  22. 22.
    El-Akouri RR, Molne J, Groth K, Kurlberg G, Brannstrom M. Rejection patterns in allogeneic uterus transplantation in the mouse. Hum Reprod. 2006;21(2):436–442.Google Scholar
  23. 23.
    Groth K, El-Akouri R, Wranning CA, Molne J, Brannstrom M. Rejection of allogeneic uterus transplant in the mouse: time-dependent and site-specific infiltration of leukocyte subtypes. Hum Reprod. 2009; 24(11):2746–2754.Google Scholar
  24. 24.
    Wranning CA, El-Akouri RR, Groth K, Molne J, Parra AK, Brannstrom M. Rejection of the transplanted uterus is suppressed by cyclosporin A in a semi-allogeneic mouse model. Hum Reprod. 2007;22(2):372–379.Google Scholar
  25. 25.
    Zhang Z, Zhu L, Quan D, et al. Pattern of liver, kidney, heart, and intestine allograft rejection in different mouse strain combinations. Transplantation. 1996;62(9):1267–1272.Google Scholar
  26. 26.
    Riederer I, Silva-Barbosa SD, Rodrigues ML, Savino W. Local antilaminin antibody treatment alters the rejection pattern of murine cardiac allografts: correlation between cellular infiltration and extracellular matrix. Transplantation. 2002;74(11):1515–1522.Google Scholar
  27. 27.
    Diaz-Garcia C, Akhi SN, Wallin A, Pellicer A, Brannstrom M. First report on fertility after allogeneic uterus transplantation. Acta Obstet Gynecol Scand. 2010;89(11):1491–1494.Google Scholar
  28. 28.
    Avison DL, DeFaria W, Tryphonopoulos P, et al. Heterotopic uterus transplantation in a swine model. Transplantation. 2009; 88(4):465–469.Google Scholar
  29. 29.
    Ramirez ER, Ramirez DK, Pillari VT, Vasquez H, Ramirez HA. Modified uterine transplant procedure in the sheep model. J Minim Invasive Gynecol 2008; 15(3):311–314.Google Scholar
  30. 30.
    Wranning CA, Enskog A, Brannstrom M. Uterus transplantation: allo-transplantation with cyclosporin A/FK506 and pregnancies after auto-transplantation in the ewe. Proceedings of the First American Conference on Reconstructive Transplant Surgery. Prospects and future of Composite Tissue Allotransplantation, Philadelphia, PA, USA, 2008; abstract.Google Scholar
  31. 31.
    Malanowska-Stega J, Schlatt S, Wagner R, Nair AR, Feret M, Del Priore G. Primate uterus allograft transplant—one year later. Fertil Steril. 2008;90(suppl 1):S169–S170.Google Scholar
  32. 32.
    Del Priore G, Stega J, Wagner A, Schlatt S. Uterus transplantation: on the edge. Semin Reprod Med. 2011;29(1):55–60.Google Scholar
  33. 33.
    Chaouat G, Lede’e-Bataille N. Dubanchet S. Immune cells in uteroplacental tissues throughout pregnancy: a brief review. Reprod Biomed Online. 2007;14(2):256–266.Google Scholar
  34. 34.
    Brannstrom M, Wranning CA, Altchek A. Experimental uterus transplantation. Hum Reprod Update. 2010;16(3):329–345.Google Scholar
  35. 35.
    Trowsdale J, Betz AG. Mother’s little helpers: mechanisms of maternal-fetal tolerance. Nat Immunol. 2006;7(3):241–246.Google Scholar
  36. 36.
    Croy BA, He H, Esadeg S, et al. Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction. 2003;126(2):149–160.Google Scholar
  37. 37.
    Davison JM, Bailey DJ. Pregnancy following renal transplantation. J Obstet Gynaecol Res. 2003: 29(4):227–233.Google Scholar
  38. 38.
    Framarino dei Malatesta M, Rossi M, Rocca B, et al. Pregnancy after liver transplantation: report of 8 new cases and review of literature. Transpl Immunol. 2006:15(4):297–302.Google Scholar
  39. 39.
    Framarino dei Malatesta M, Rossi M, Rocca B, et al. Fertility following solid-organ transplantation. Transplant Proc 2007; 39(6):2001–2004.Google Scholar
  40. 40.
    Alonso A, Fernandez C, Villaverde P, et al. Kidney-pancreas transplants: is it so difficult to start a program? Transplant Proc. 2005;37(3):1455–1456.Google Scholar
  41. 41.
    Meregalli E, Biggioggero M, Borghi O, Meroni P, Cimaz R. In vivo effects of maternal immunosuppression during pregnancy on the immune function of newborn infants. Arh Hig Rada Toksikol. 2005;56(2):151–156.Google Scholar
  42. 42.
    Bedaiwy MA, Shahin AY, Falcone T. Reproductive organ transplantation: advances and controversies. Fertil Steril. 2008; 90: 2031–2055.Google Scholar
  43. 43.
    Doria A, Iaccarino L, Sarzi-Puttini P, et al. Estrogens in pregnancy and systemic lupus erythematosus. Ann N Y Acad Sci. 2006;1069:247–256.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004;1024:138–146.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993;14(7): 353–356.Google Scholar
  46. 46.
    McKay DB, Josephson MA. Pregnancy in recipients of solid organs—effects on mother and child. N Engl J Med. 2006; 354(12):1281–1293.Google Scholar
  47. 47.
    Framarino dei Malatesta ML, Poli L, Pierucci F et al: Pregnancy and kidney transplantation: clinical problems and experience. Transplant Proc. 1993; 25(3):2188–2189.Google Scholar
  48. 48.
    Armenti VT, Radomski JS, Moritz MJ, et al. Report from the National Transplantation Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2004; 18:103–114.Google Scholar
  49. 49.
    Radomsky JS, Ahlswede BA, Jarrel BE, et al. Outcome of 500 pregnancies in 335 female kidney, liver and heart transplant recipients. Transplant Proc. 1995; 27(1):1089–1090.Google Scholar
  50. 50.
    Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy. Choices for infant and maternal health. Drugs 2002;62(16):2361–2375.Google Scholar
  51. 51.
    Armenti VT, Radomski JS, Moritz MJ, et al. Report from National Transplantation Pregnancy Register (NTPR): outcomes of pregnancy after transplantation. Clin Transpl. 2002; 16: 121–130.Google Scholar
  52. 52.
    Jain A, Venkataramanam R, Fung JJ, et al. Pregnancy after liver transplantation under tacrolimus. Transplantation. 1997;64(4): 559–565.Google Scholar
  53. 53.
    Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004; 4(2):222–230.Google Scholar
  54. 54.
    Bar J, Stahl B, Hod M, Wittenberg C, Pardo J, Merlob P. Is immunosuppression therapy in renal allograft recipients teratogenic. A single centre experience. Am J Med Genet A. 2003; 116A(1):31–36Google Scholar
  55. 55.
    Kallen B, Westgren M, Aberg A, Otterblad Olausson P. Pregnancy outcome after maternal organ transplantation in Sweden. Br J Obstet Gynaecol. 2005; 112(7):904–909.Google Scholar
  56. 56.
    Groth K, Brännström M, Mölne J, Wranning CA. Cyclosporine A exposure during pregnancy in mice: effects on reproductive performance in mothers and offspring. Hum Reprod. 2010; 25(3):697–704.Google Scholar
  57. 57.
    Mason RJ, Thomson AW, Whiting PH, et al. Cyclosporineinduced fetotoxicity in the rat. Transplantation. 1985;39(1):9–12.Google Scholar
  58. 58.
    Fein A, Vechoropoulos M, Nebel L. Cyclosporin-induced embryotoxicity in mice. Biol Neonate. 1989; 56(3):165–173.Google Scholar
  59. 59.
    Esquifino AI, Moreno ML, Agrasal C, Villanua MA. Effects of cyclosporine on ovarian function in sham-operated and pituitary-grafted young female rats. Proc Soc Exp Biol Med. 1995; 208(4):397–403.Google Scholar
  60. 60.
    Gore-Langton RE. Cyclosporine differentially affects oestrogen and progestin synthesis by rat granulosa cells in vitro. Mol Cell Endocrinol. 1988; 57(3):187–198.Google Scholar
  61. 61.
    Robertson SA. Immune regulation of conception and embryo implantation—all about quality control? J Reprod Immunol. 2010;85(1):51–57.Google Scholar
  62. 62.
    Kaminski P, Bobrowska K, Pietrzak B, Bablok L, Wielgos M. Gynaecological issues after organ transplantation. Neuroendocrinol Lett. 2008;29(6):852–856.Google Scholar
  63. 63.
    Lessan-Pezeshki M, Ghazizadeh S, Khatami MR, et al. Fertility and contraceptive issues after kidney transplantation in women. Transplant Proc. 2004; 36(5):1405–1406.Google Scholar
  64. 64.
    Parolin MB, Rabinovitz I, Urbanetz AA, Scheidemantel C, Cat ML, Coelho JC. Impact of successful liver transplantation on reproductive function and sexuality in women with advanced liver disease. Transplant Proc. 2004; 36(4):943–944.Google Scholar
  65. 65.
    Phocas I, Sarandacou A, Kassanos D, Rizos D, Tserkezis G, Koutsikos D. Hormonal and ultrasound characteristic of menstrual function during chronic hemodialysis and after successful renal transplantation. Int J Gynecol Obst. 1992;37(1):19–28.Google Scholar
  66. 66.
    El-Akouri RR, Kurlberg G, Brannstrom M. Successful uterine transplantation in the mouse: pregnancy and post-natal development of offspring. Hum Reprod. 2003;18(10):2018–2023.Google Scholar
  67. 67.
    Racho El-Akouri R, Wranning CA, Molne J, Kurlberg G, Brannstrom M. Pregnancy in transplanted mouse uterus after long-term cold ischaemic preservation. Hum Reprod. 2003;18(10):2024–2030.Google Scholar
  68. 68.
    Diaz-Garcia C, Akhi SN, Wallin A, Pellicer A, Brannstrom M. First report on fertility after allogeneic uterus transplantation. Acta Obstet Gynecol Scand. 2010;89(11):1491–1494.Google Scholar
  69. 69.
    Wranning CA, Akhi SN, Diaz-Garcia C, Brännström M. Pregnancy after syngeneic uterus transplantation and spontaneous mating in the rat. Hum Reprod. 2011;26(3):553–558.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Wieers G, Gras J, Bourdeaux C, Truong DQ, Latinne D, Reding R. Monitoring tolerance after human liver transplantation. Transpl Immunol. 2007;17(2):83–93.Google Scholar
  71. 71.
    Fritzsching E. Kunz P, Maurer B, Poschl J, Fritzsching B. Regulatory T cells and tolerance induction. Clin Transplant. 2009; 23(suppl 21):10–14.Google Scholar
  72. 72.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155(3):1151–1164.Google Scholar
  73. 73.
    Kang SM, Tang Q, Bluestone JA. CD4+ CD25+ regulatory T cells in transplantation: progress, challenges and prospects. Am J Transplant. 2007; 7(6):1457–1463.Google Scholar
  74. 74.
    Golshayan D, Jiang S, Tsang J, Garin MI, Mottet C, Lechler RI. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood. 2007;109(2):827–835.Google Scholar
  75. 75.
    Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007;7(8):585–598.Google Scholar
  76. 76.
    Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med 2005; 353(22):2342–2351.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Braudeau C, Racape M, Giral M, et al. Variation in numbers of CD4 + CD25highFOXP3+ T cells with normal immuno-regulatory properties in long-term graft outcome. Transpl Int. 2007; 20(10): 845–855.Google Scholar
  78. 78.
    Bestard O, Cruzado JM, Mestre M, et al. Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates. J Immunol. 2007;179(7):4901–4909.Google Scholar
  79. 79.
    Ostensen M, & Villiger PM. Immunology of pregnancy—pregnancy as a remission inducing agent in rheumatoid arthritis. Transpl Immunol. 2002; 9(9–4):155–160.Google Scholar
  80. 80.
    Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod. 2004;10(5):347–353.Google Scholar
  81. 81.
    Waid TH, Thompson JS, Siemionow M, Brown SA. T10B9 monoclonal antibody: a short-acting nonstimulating monoclonal antibody that spares gammadelta T-cells and treats and prevents cellular rejection. Drug Des Devel Ther. 2009;3:205–212.Google Scholar
  82. 82.
    Kawai T, Cosimi AB, Spitzer TR, et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008; 358(4):353–361.Google Scholar

Copyright information

© Society for Reproductive Investigation 2012

Authors and Affiliations

  • Srdjan Saso
    • 1
  • Sadaf Ghaem-Maghami
    • 2
  • Jayanta Chatterjee
    • 1
  • Nancy Brewig
    • 1
  • Laszlo Ungar
    • 3
  • J. Richard Smith
    • 2
  • Giuseppe Del Priore
    • 4
    Email author
  1. 1.Department of Surgery and Cancer, Institute of Reproductive & Developmental BiologyImperial College London, Hammersmith Hospital CampusLondonUK
  2. 2.West London Gynaecological Cancer Centre, Queen Charlotte’s Hospital, Hammersmith Hospital CampusImperial College LondonLondonUK
  3. 3.Department of Gynaecologic OncologySt Stephen HospitalBudapestHungary
  4. 4.Division of Gynecologic Oncology, School of MedicineIndiana UniversityIndianapolisUSA

Personalised recommendations