Abstract
The prospect of in utero fetal transplantation represents a potential major step forward in the management of patients with congenital hematological, metabolic and immunological disorders. Successful allogeneic in utero transplantations (IUTs) of hematopoietic stem cells HSC) have been reported in several animal models. The first successful transplantation in man was reported by Touraine et al. in 1989 in a case of bare lymphocyte syndrome. Since then more than 35 IUTs have been published or reported at national or international meetings. The transplantations have been reported for a variety of indications, at various gestational ages, and with different sources of the transplant. All cases of IUT performed in fetuses with normal immunological function have failed, and unequivocal engraftment could so far only be demonstrated in fetuses suffering from severe immunodeficiency disorders. Most publications reviewing in utero stem cell transplantation have stated that the fetus is the ideal candidate for therapy due to its immature immune system, which should permit the transplantation of non-human leukocyte antigen (HLA) matched cells and allow the developing fetus to recognize the donor cells as “self” (Flake 1986; Crombleholme et al. 1990, 1991; Flake et al. 1991; Touraine et al. 1991; Zanjani et al. 1991; Zanjani 1992; Westgren and Ringden 1994; Jones et al. 1996; Flake and Zanjani 1997, 1999; Surbek et al. 1999). In addition, there should be abundant and readily available hematopoietic niches from donor cells to engraft secondary to fetal growth. However, when one considers that all attempted allogeneic transplantations in immunocompetent human fetuses have failed, then doubts have to be cast on these theories and the whole concept needs to be reappraised. The purpose of this chapter is to provide a critical review of the clinical progress in this field.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Andrews RG, Bensinger WI, Knitter GH et al (1992) The ligand for c-kit, stem cell factor, stimulates the circulation of cells that engraft lethally irradiated baboons. Blood 80: 2715–2720
Auguset C (1971) Onset of lymphocyte function in the developing human fetus. Pediatr Res 5: 539–547
Bambach BJ, Moser HW, Blakemore K et al (1997) Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy. Bone Marrow Transplant 19: 399–402
Blomberg M, Rao S, Reilly J et al (1998) Repetitive bone marrow transplantation in nonmyeloablated recipients. Exp Hematol 26: 320–324
Buckley RH, Schiff SE, Schiff RI et al (1999) Hematopoietic stem cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 340: 508–516
Carrier E, Lee TH, Busch MP, Cowan MJ (1995) Induction of tolerance in nondefective mice after in utero transplantation of major histocompatibility complex-mismatched fetal hematopoietic stem cells. Blood 86: 4681–4690
Cowan MJ, Golbus M (1994) In utero hematopoietic stem cell transplants for inherited diseases. Am J Pediatr Hematol Oncol 16: 35–42
Cowan MJ, Tarantal AF, Capper J, Harrison M, Garovoy M (1996) Long term engraftment following in utero T cell depleted parental marrow transplantation into fetal rhesus monkeys. Bone Marrow Transplant 17: 1157–1165
Crombleholme TM, Harrison MR, Zanjani ED (1990) In utero transplantation of hematopoietic stem cells in sheep: the role of T cells in engraftment and graft-versus-host disease. J Pediatr Surg 25: 885–892
Crombleholme TM, Langer JC, Harrison MR, Zanjani ED (1991) Transplantation of fetal cells. Am J Obstet Gynecol 164: 218–229
Diukman R, Golbus M (1992) In utero stem cell therapy. J Reprod Med 37: 515–520
Ebert U, Loffler H, Kirch W (1997) Cytotoxic therapy and pregnancy. Pharm Ther 74: 207–220
Ek S, Westgren M, Ringden O et al (1994) Infectious screening in fetal stem cell collection. Fetal Diagn Ther 9: 357–362
Ekhterae D, Crumbleholme T, Karson E, Harrison MR, Anderson WF, Zanjani ED (1990) Retroviral vector-mediated transfer of the bacterial neomycin resistance gene into fetal and adult sheep and human hematopoietic progenitors in vitro. Blood 75: 365–369
Flake A (1986) Transplantation of fetal hematopoietic stem cells in utero: the creation of hematopoietic chimeras. Science 223: 776–778
Flake AW, Zanjani ED (1997) In utero hematopoietic stem cell transplantation. A status report. JAMA 278: 932–937
Flake AW, Zanjani E (1999) In utero hematopoietic stem cell transplantation: ontogenic opportunities and biological barriers. Blood 54: 2179–2191
Flake A, Harrison M, Zanjani E (1991) In utero stem cell transplantation. Exp Hematol 19: 1061–1064
Flake AW, Roncarolo M-G, Puck JM (1996) Treatment of X-linked severe combined immunodeficiency in utero transplantation of paternal bone marrow. N Engl J Med 335: 1806–1810
Fletcher JC (1992) Fetal therapy, ethics and public policy. Fetal Diagn Ther 7: 158–168
Gale R (1987) Development of the immune system in human fetal liver. Thymus 10: 45–56
Gathings WE, Lawton AR, Cooper MD (1977) Immunofluorescent studies of the development of pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur J Immunol 7: 804–810
Hajdu K, Golbus MS (1993) Stem cell transplantation. West J Med 159: 356–359
Harrison M (1989) In-utero transplantation of fetal liver haemopoietic stem cells in monkeys. Lancet 2: 1425–1427
Hayward A, Ambruso D, Battaglia F et al (1998) Microchimerism and tolerance following intrauterine transplantation and transfusion for alpha-thalassemia-1. Fetal Diagn Ther 13: 8–14
Jaleco AC, Blom B, Res P et al (1997) Fetal liver contains committed NK progenitors, but is not a site for development of CD34+ cells into T cells. J Immunol 159: 694–702
Jankowski RA, Ildstad ST (1997) Chimerism and tolerance: from freemartin cattle and neonatal mice to humans. Hum Immunol 52: 155–161
Jones DR, Bui TH, Anderson EM et al (1996) In utero haematopoietic stem cell transplantation: current perspectives and future potential. Bone Marrow Transplant 18: 831–837
Lanfranchi A, Neva A, Tettoni K, Veradi R, Mazzolari E, Wengler G et al (1998) In utero transplantation (IUT) of parental CD34+ cells in patients affected by primary immunodeficiencies. Bone Marrow Transplant 21: S127
Lanier LL (1995) The role of natural killer cells in transplantation. Curr Opin Immunol 7: 626–631
Lansdorp PM (1995) Telomere length and proliferation potential of hematopoietic stem cells. Stem Cell Trans 108: 1–6
Leung W, Blakemore K, Jones R-J et al (1999) A human murine chimera for in utero human hematopoietic stem cell transplantation. Biol Blood Marrow Transpl 5: 1–7
Linch D, Rodeck C, Nicolaides K, Jones H, Brent L (1986) Attempted bone-marrow transplantation in a 17-week fetus. Lancet 27: 1453
Lindton B, Markling L, Ringden O, Kjaeldgaard A, Gustafsson O, Westgren M (2000) Mixed lymphocyte culture of human fetal liver cells. Fetal Diag Ther 15: 71–78
McCullough L, Chervenaek F (1994) Ethics in obstetrics and gynecology. Oxford University Press, New York
Monni G, Ibba RM, Zoppi MA, Fions M (1998) In utero stem cell transplantation. Croat Med 39: 220–223
Muench MO, Cupp J, Polakoff J, Roncarolo MG (1994) Expression of CD33, CD38, and HLA-DR on CD34+ human fetal liver progenitors with a high proliferative potential. Blood 83: 3170–3181
Opie TM, Shields LE, Andrews RG (1998) Cell surface antigen expression in early and term gestation fetal hematopoietic progenitor cells. Stem Cells 16: 343–348
Peeters MJ, Patijn GA, Lieber A, Meuse L, Kay MA (1996) Adenovirus-mediated hepatic gene transfer in mice: comparison of intravascular and biliary administration. Hum Gene Ther 7: 1693–1699
Peschle C (1997) In utero transplantation of purified stem cells from an HLA identical sibling into a b-thalassemia embryo. In utero stem cell transplantation and gene therapy, 2nd international meeting, Nottingham
Randall T (1993) National registry seeks scarce data on pregnancy outcomes during chemotherapy. JAMA 260: 323
Rao SS, Peters SO, Crittenden RB et al (1997) Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment. Exp Hematol 25: 113–121
Riddell SR, Elliott M, Lewinsohn DA et al (1996) T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients (see comments). Nat Med 2: 216–223
Roodman GH, Kuehl TJ, Vanderberg JL, Muirhead DY (1991) In utero bone marrow transplantation of fetal baboons with mismatched adult bone marrow. Blood Cells 17: 367–375
Shields L, Andrews R (1999) In utero engraftment by allogenic CD34+ marrow cells in nonhuman primates: relationship to the absolute number of cells transplanted. J Soc Gynecol Invest 6: 186A
Shields LE, Andrews RG (1998) Gestational age changes in circulating CD34+ hematopoietic stem/progenitor cells in fetal cord blood. Am J Obstet Gynecol 178: 931–937
Shields LE, Kiem H-P, Andrews RG (2000) A comparison of preterm and term gestation umbilical cord blood CD34+ hematopoietic progenitor cells (HPC) as targets for retroviral mediated gene transfer. Am J Obstet Gynecol (in press)
Silverstein A, Uhr J, Kraner K (1963) Fetal Response to antigenic stimulus: antibody production by the fetal lamb. J Exp Med 117: 799–812
Slavin S, Naparstek E, Ziegler M, Lewin A (1992) Clinical application of intrauterine bone marrow transplantation for treatment of genetic diseases — feasibility studies. Bone Marrow Transplant 9: 189–190
Stark JH, Smit JA, Neethling FA, Nortman PJ, Myburgh JA (1991) Immunological compatibility between the chacma baboon and man. Transplantation 52: 1072–1078
Stites DP, Carr MC, Fudenberg HH (1974) Ontogeny of cellular immunity in the human fetus: development of responses to phytohemagglutinin and to allogenic cells. Cell Immunol 11: 257–271
Surbek DV, Gratwohl A, Holzgreve W (1999) In utero hematopoietic stem cell transfer: current status and future strategies. Eur J Obstet Gynecol 85: 109–115
Tavassoli M (1991) Embryonic and fetal hemopoiesis: an overview. Blood Cells 1: 269–281
Thilaganthan B, Nicoliades K (1993) Intrauterine bone-marrow transplantation at 12 gestation. Lancet 342: 243
Thilaganathan B, Abbas A, Nicolaides KH (1993) Fetal blood natural killer cells in human pregnancy. Fetal Diagn Ther 8: 149–153
Thilaganathan B, Nicolaides KH, Morgan G (1994) Subpopulations of CD34-positive haemopoietic progenitors in fetal blood. Br J Haematol 87: 634–636
Touraine JL (1990) In utero transplantation of stem cells in humans. Nouv Rev Fr Hematol 32: 441–444
Touraine JL (1996) Treatment of human fetuses and induction of immunological tolerance in humans by in utero transplantation of stem cells into fetal recipients. Acta Haematol 96: 115–119
Touraine JL, Raudrant D, Royo C et al (1989) In utero transplantation of stem cells in the bare lymphocyte syndrome. Lancet i: 1382
Touraine JL, Raudrant D, Royo C et al (1991) In utero transplantation of fetal liver stem cells in humans. Blood Cells 17: 379–387
Touraine JL, Raudrant D, Rebaud A et al (1992) In utero transplantation of stem cells in humans: immunological aspects and clinical follow-up of patients. Bone Marrow Transplant 1: 121–126
Van Furth R, Schuit H, Hijmans W (1965) The immunological development of the human fetus. J Exp Med 122: 1173–1187
Wengler GS, Lanfranchi A, Frusca T et al (1996) In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDXI). Lancet 348: 1484–1487
Westgren M, Ek S, Bui TH et al (1994) Establishment of a tissue bank for fetal stem cell transplantation. Acta Obstet Gynecol Scand 73: 385–390
Westgren M, Ek S, Jansson B et al (1997) Tissue distribution of transplanted fetal liver cells in the human fetal recipient. Am J Obstet Gynecol 176: 49–53
Westgren M, Ringden O, Eik Nes S et al (1996) Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies. Transplantation 61: 1176–1179
Westgren M, Ringden OI (1994) Fetal to fetal transplantation. Acta Obstet Gynecol Scand 73: 371–373
Zanjani E (1992) The fetus as an optimal donor and recipient of hemopoietic stem cells. Bone Marrow Transplant 10: 107–114
Zanjani ED, Mackintosh FR, Harrison MR (1991) Hematopoietic chimerism in sheep and nonhuman primates by in utero transplantation of fetal hematopoietic stem cells. Blood Cells 17: 349–363
Zanjani ED, Ascensao JL, Tavassoli M (1992) Homing of liver-derived hemopoietic stem cells to fetal bone marrow. Trans Assoc Am Phys 105: 7–14
Zanjani ED, Ruthven A, Ruthven J et al (1994) In utero hematopoietic stem cell transplantation results in donor specific tolerance and facilitates postnatal boosting of donor cell levels. Blood 84: 100–12
Zanjani ED, Almeida-Porada G, Ascensano JL et al (1997) Transplantation of hematopoietic stem cells in utero. Stem Cells 15: 79–93
Zemlickis D, Lishner M, Degendorfer P et al (1992) Fetal outcome after in utero exposure to cancer chemotherapy. Arch Intern Med 152: 573–576
Ziegler BL, Valtieri M, Porada GA et al (1999) KDR receptor: a key marker defining hematopoietic stem cells. Science 285: 1553–1558
Editor information
Rights and permissions
Copyright information
© 2001 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Westgren, M., Shields, L.E. (2001). In Utero Stem Cell Transplantation in Humans. In: Holzgreve, W., Lessl, M. (eds) Stem Cells from Cord Blood, in Utero Stem Cell Development and Transplantation-Inclusive Gene Therapy. Ernst Schering Research Foundation Workshop, vol 33. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-04469-8_13
Download citation
DOI: https://doi.org/10.1007/978-3-662-04469-8_13
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-04471-1
Online ISBN: 978-3-662-04469-8
eBook Packages: Springer Book Archive