Abstract
The morbidity and mortality associated with postnatal HSCT, toxicity of HSCT conditioning regimens, lifelong immunosuppressive therapy, and lack of compatible donors discourages many patients and physicians from utilizing postnatal HSCT as a treatment for congenital disease. Non-myeloablative in utero HSCT is now being considered as an alternate treatment with the hope that it will be more therapeutic with less toxicity to a wider spectrum of patients with congenital disorders. Prenatal stem cell transfer may eliminate many of the risks and hazards associated with postnatal HSCT, as the fetus may be less reactive than an immunologically mature individual such that tolerance to donor cells could be developed. GVHD and rejection of postnatal therapeutic grafts may be minimized thus reducing or eliminating altogether the need for postnatal myeloablation and immunosuppression. Much work must be done both in animal studies as well as in clinical trials. By using well-designed murine models such as the β-thalassemic mouse outlined above, we believe we can determine the optimal conditions for non-myeloablative postnatal transplants with allogeneic or haplocompatible HSC following prenatal tolerance induction with these cells. In addition, we may answer basic immunology questions regarding the development and regulation of immunity and tolerance in both mice and humans.
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References
Krivit W, Shapiro E, Kennedy W et al: Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. New Engl J Med. 322(1):28, 1990
Krivit W, Pierpont ME, Ayaz K et al: Bone-marrow transplantation in the Maroteaux-Lamy syndrome (mucopolysaccharidosis VI). Biochemical and clinical status 24 months after transplantation. New Engl J Med. 311(25):1606, 1984
Parkman R: The application of bone marrow transplantation to the treatment of genetic diseases. Science 232(4756):1373, 1986
Sullivan KM: Current status of bone marrow transplantation. Transplant Proc. 21(3 Suppl 1):41, 1989
Clark J: The challenge of bone marrow transplantation. Mayo Clin Proc. 65(1):111, 1990
Sasazuki T, Juji T, Morishima Y et al: Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program. New Engl J Med. 339(17):1177, 1998
Exner BG, Acholonu I, Ildstad ST: Hematopoietic chimerism, tolerance induction and graft-versus-host disease: considerations for composite tissue transfer. Transplant Proc. 30(6):2718, 1998
Ellison C, Gartner J: Acute, lethal graft-versus-host disease in a F1-hybrid model using grafts from parental-strain, T-cell receptor-delta gene knockout donors. Scand J Immunol. 48(3):272, 1998
Asplund S, Gramlich TL: Chronic mucosal changes of the colon in graftversus-host disease. Mod Pathol. 11(6):513, 1998
Nagler A, Condiotti R, Nabet C et al: Selective CD34+-T cell depletion does not prevent graft-versus-host disease. Transplantation 66(1):138, 1998
Klingebiel T, Schlegel PG: GVHD: overview on pathophysiology, incidence, clinical and biological features. Bone Marrow Transplant 21(Suppl 2):S45, 1998
Rebecca H. Buckley, Sherrie E. Schiff, Richard I. Schiff, M. Louise Markert, Larry W. Williams, Joseph L. Roberts, Laurie A. Myers, Frances E. Ward Hematopoietic Stem-Cell Transplantation for the Treatment of Severe Combined Immunodeficiency. The New England Journal of Medicine, February 18, 1999,Vol. 340, No. 7 N Engl J Med 1999;340:508–16.
Giardini C, Lucarelli G. Bone marrow transplantation for beta-thalassemia. Hematol Oncol Clin North Am 1999, Oct 13 (5): 1059.
Lucarelli G, Galimberti M, Giardini C, Polchi P, Angelucci E, Baronciani D, Erer B, Graziev D: Bone marrow transplantation in thalassemia. The experience of Pesaro. Ann NY Acad Sci 850:270, 1998
Lucarelli G, Clift RA, Galinberti M et al: Marrow transplantation for patients with thalassemia: results in class 3 patients. Blood 87(5):2082, 1996
Vermylen C, Cornu G, Ferster A, Brichard B, Ninane J, Ferrant A, Zenebergh A, Maes P, Dhooge C, Benoit Y, Beguin Y, Dresse MF, Sariban E Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium.Bone Marrow Transplant1998 Jul;22(1):1–6
Charles Peters, Elsa G. Shapiro, James Anderson, P. Jean Henslee-Downey, Martin R. Klemperer, Morton J. Cowan, E. Fred Saunders, Pedro A. deAlarcon, Clare Twist, James B. Nachman, Gregory A. Hale, Richard E. Harris, Marta K. Rozans, Joanne Kurtzberg, Guy H. Grayson, Thomas E. Williams, Carl Lenarsky, John E. Wagner, William Krivit, and the members of The Storage Disease Collaborative Study Group. Hurler Syndrome: II. Outcome of HLAGenotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in Fifty-Four Children: Blood, Vol. 91 No. 7 (April 1), 1998: pp. 2601–2608.
Tavassoli M. Embryonic and fetal hemopoiesis: an overview. Blood Cells 1991;1:269–81
Renda MC, Fecarotta E, Dieli F, Markling L, Westgren M, Damiani G, Jakil C, Picciotto F, Maggio A: Evidence of alloreactive T lymphocytes in fetal liver: implications for fetal hematopoietic stem cell transplantation.Bone Marrow Transplant2000 Jan;25(2):135–41.
Blazar BR, Taylor PA, Vallera DA: In utero transfer of adult bone marrow cells into recipients with severe combined immunodeficiency disorder yields lymphoid progeny with T- and B-cell functional capabilities. Blood 86(11):4353, 1995
Archer DR, Turner CW, Yeager AM, Fleming WH: Sustained multilineage engraftment of allogeneic hematopoietic stem cells in NOD/SCID mice after in utero transplantation. Blood 90:3222, 1997
Bruce R. Blazar, Patricia A. Taylor, Ron McElmurry, Lina Tian, Angela Panoskaltsis-Mortari, Sylvia Lam, Chris Lees, Thomas Waldschmidt, and Daniel A. Valiera: Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow Via In Utero or Postnatal Transfer. Blood, Vol. 92 No. 10 (November 15), 1998: pp. 3949–3959
Fleischman R, Mintz B: Prevention of genetic anemias in mice by microinjection of normal hematopoietic cells into the fetal placenta. Proc Natl Acad Sci USA 76:5736, 1979
Blanchet JP, Fleischman RA, Mintz B: Murine adult hematopoietic cells produce adult erythrocytes in fetal recipients. Developmental Genetics 3:197, 1982
Blazar BR, Taylor PA, Valiera DA: Adult bone marrow-derived pluripotent hematopoietic stem cells are engraftable when transferred in utero into moderately anemic fetal recipients. Blood 85(3):833, 1995
Soper BW, Duffy T, Barker JE: Corrective therapy for mucopolysaccharidosis type VII by transplantation of syngeneic lineagelowSCA-lDghighhoecHSCT 33342lowmarrow into W41/W41/gusmps/gusmpsrecipients. Blood 90(10):364a, 1997
Zanjani ED, Almeida-Porada G, Flake AW: The human/sheep xenograft model: a large animal model of human hematopoiesis.Int J Hematol1996Apr;63(3):179–92
Zanjani ED, Ascensao JL, Flake AW, Harrison MR, Tavassoli M: The fetus as an optimal donor and recipient of hemopoietic stem cells. Bone Marrow Transplant 10:107, 1992 (suppl 1)
Mychaliska GB, Rice HE, Tarantal AF et al: In utero hematopoietic stem cell transplants prolong survival of postnatal kidney transplantation in monkeys. J Pediatr Surg. 32(7):976, 1997
Flake AW and Zanjani ED: In Utero Hematopoietic Stem Cell Transplantation: Ontogenic Opportunities and Biological Barriers. Blood (94) 7: 2179–2191, October 1, 1999.
Touraine JL, Raudrant D, Rebaud A, Roncarolo MG, Laplace S, Gebuhrer L, Betuel H, Frappaz D, Freycon F, Zabot MT, Dubernard JM: In utero transplantation of stem cells in humans: Immunological aspects and clinical follow-up of patients. Bone Marrow Transplant 1:121, 1992.
Touraine JL, Raudrant D, Royo C, Rebaud A, Roncarolo MG, Souillet G, Philippe N, Touraine F, Betuel H: In-utero transplantation of stem cells in bare lymphocyte syndrome. Lancet 1:1382, 1989.
Flake A, Roncarolo M-G, Puck J, Almeida-Porada G, Evans M, Johnson M, Abella E, Harrison D, Zanjani E: Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. N Engl J Med 335:1806, 1996.
Wengler G, Lanfranchi A, Frusca T, Verardi R, Neva A, Brugnoni D, Gilliani S, Fiorini M, Mella P, Guandalini F, Mazzolari E, Pecorelli S, Notarangelo L, Porta F, Ugazio A: In-utero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1). Lancet 348:1484, 1996.
Gil J, Porta F, Bartolome J, Lafranchi A, Verardi R, Notarangelo LD, Carlo-Stella C, Rodriguez R, Rodriguez JJ, Gurbindo D, Cela E, Zucca A, Fernandez-Cruz E, Ugazio AG Immune reconstitution after in utero bone marrow transplantation in a fetus with severe combined immunodeficiency with natural killer cells.Transplant Proc1999 Sep;31(6):2581).
Touraine J: 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, 1996
Harrison MR, Albanese C, Muench M, Farrell J, Lopoo J, Barcena A: Allogeneic in utero transplantation of CD34+THY-1+ bone marrow derived hematopoietic stem cells (HSC) in a fetus with chronic granulomatous disease. Proceedings of the International Fetal Medicine and Surgery Society. Carlisle, UK, 1999
Alan W. Flake and Esmail D. Zanjani: In Utero Hematopoietic Stem Cell Transplantation: Ontogenic Opportunities and Biologic Barriers. Blood, Vol. 94 No. 7 (October 1), 1999: pp. 2179–2191
Monni G; Ibba RM; Zoppi MA; Floris M: Purified paternal CD34+ HSC at 10 weeks gestation, no engraftment, normal birth. Croat Med J 1998 Jun;39(2):220–223.
Hayward A, Ambruso D, Battaglia F, Donlon T, Eddelman K, Giller R, Hobbins J, Hsia YE, Quinones R, Shpall E, Trachtenberg E, Giardina P: Microchimerism and tolerance following intrauterine transplantation and transfusion for-thalassemia-1. Fetal Diagn Ther 13:8, 1998.
Thalaganthan B, Nicolaides K: Intrauterine bone-marrow transplantation at 12 weeks gestation. Lancet 342:243, 1993.
Flake AW, Zanjani ED: In Utero Transplantation, in Forman SJ, Bloom KG, Thomas ED (eds): Hematopoietic Cell Transplantation (ed 2). Malden, MA, Blackwell Science, 1999, p 444.
Owen RD: Immunogenetic consequences of vascular auestomoses between bovine cattle twins. Science 10:400, 1945
Cragle RG, Stone WH: Preliminary results of kidney grafts between cattle chimeric twins. Transplantation 5:328, 1967
asBillingham RE, Brent L, Madawar PB: Actively acquired tolerance of foreign cells. Nature 4379:603, 1953
Billingham R, Brent L, Madawar PB: Quantitative studies on tissue transplantation immunity. Actively acquired tolerance. Phil Trans Roy Soc(lon) B 239:357, 1956
Renda MC, Fecarotta E, Dieli F, Markling L, Westgren M, Damiani G, Jakil C, Picciotto F, Maggio A: Evidence of alloreactive T lymphocytes in fetal liver: implications for fetal hematopoietic stem cell transplantation.Bone Marrow Transplant2000 Jan;25(2):135–41.
Guidos CJ, Danska JS, Fathman CG, Weissman IL: T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J Exp Med. 172(3):835, 1990
Sarzotti M, Robbins DS, Hoffman PM: Induction of protective CU responses in newborn mice by a murine retrovirus. Science 271(5256):1726–1728, 1996
Kappler JW, Roehm N, Marrack P: T cell tolerance by clonal elimination in the thymus. Cell 49(2):273, 1987
Fuchs EJ, Matzinger P: B cells turn off virgin but not memory T cells. Science 258:1156, 1992
Ridge JP, Fuchs EJ, Matzinger P: Neonatal tolerance revisited: Turning on newborn T cells with dendritic cells. Science 271(5256):1723, 1996
Forsthuber T, Yip HC, Lehmann PV: Induction of TH1 and TH2 immunity in neonatal mice. Science 271(5256):1728, 1996
Carrier E, Gilpin E, Lee TH, Busch MP, Zanetti M: Microchimerism does not induce tolerance after in utero transplantation and may lead to the development of alloreactivity.J Lab Clin Med2000 Sep;136(3):22435
Flake A, Zanjani E: Cellular therapy. New trends and controversies in fetal diagnosis and therapy. Obstet Gynecol Clin North Am 24:159, 1997
Stewart FM, Crittenden RB, Lowery PA, Quesenberry PJ et al: Long-term engraftment of normal and post-5-fluorouracil murine bone marrow into normal nonmyeloablated mice. Blood 81:2566, 1993
Quesenberry PJ, Ramshaw H, Crittenden RB et al: Engraftment of normal murine marrow into nonmyeloablated host mice. Blood Cells 20(23):348, 1994
Archer DR, Hester LE, Gu Y et al: Successful in utero engraftment of allogeneic hematopoietic cells in murine a-thalassemia. Blood 92(10):267a, 1998
Barker JE, Compton ST: Hematopoietic repopulation of adult mice with betathalassemia. Blood 83(3):828–832, 1994.
Donahue J, Kuypers F, Witkowska E, Carrier E et al: Engraftment and tolerance following in utero transplantation in ß-thalassemic mice. Blood 92(10):286b, 1998
Hedrick H, Rice H, MacGillivray T, Beater J, Zanjani E, Flake A. Hematopoietic chimerism achieved by in utero hematopoietic stem cell injection does not induce donor-specific tolerance for renal allografts in sheep. Transplantation 1994; 58: 110–111.
Fuchs EJ, Matzinger P. B cells turn off virgin but not memory T cells. Science 1992; 258: 1156–1159.
Matzinger P. Tolerance, danger, and the extended family. Ann Rev Immunol 1994; 12: 991–1045.
Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance revisited. Science 1996; 271: 1723–1726.
Bambach BJ, Moser HW, Blakemore K, Corson VL, Griffin CA, Noga SJ,Perlman EJ, Zuckerman R, Wenger DA, Jones RJ. Engraftment following in utero bone marrow transplantation for globoid leukodystrophy. Bone Marrow Transplant 1997; 19 (4): 399–402.
Sarzotti M, Robbins DS, Hoffman PM. Induction of protective CTL responses in newborn mice by murine retrovirus. Science 1996; 271: 1726–1728.
Sykes M, Chester GH, Sachs DH. Effect of T-cell depletion in radiation bone marrow chimeras. J Exp Med 1988; 168: 661–668.
Drobyski WR, Majewski D. Donor gamma delta T lymphocytes promote allogeneic engraftment across the major histocompatibility barrier in mice. Blood 1997; 89(3): 1100–1109.
Krenger W, Snyder K, Byon J, Falzarano G, Ferrara J. Polarized type 2 allogeneic CD+ and CD8+ donor T cells failed to induce experimental acute graft-versus-host disease. J Immunol 1995; 155: 585–593.
Fu F, Li Y, Qian S, Lu L, Chambers F, Starzl T, Fung J, Thomson A. Costimulatory molecule-deficient dendritic cell progenitors (MHC II+, CD8Odim, CD86-) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation 1996; 62: 659–665.
Lu L, Li W, Zhong G, Qian S, Fung J, Thomson A, Starzl T. Increased apoptosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus antiCD4OL mAb. Transplantation 1999; 68: 747–757.
Lu L, McCaslin D, Starzl T, Thomson A. Bone marrow-derived dendritic cell progenitors (NLDC 145+, MHCII+, B7–1dim, B7–2-) induce alloantigens-specific hyporesponsiveness in murine lymphocytes. Transplantation 1995; 60: 1539–1545.
Kikuchi T, Moore MA, Crystal RG. Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood 2000; 96: 91–99.
Korbutt GS, Elliott JF, Rajotte RV. Cotransplantation of allogeneic islets with allogenic testicular cell aggregate allows long-term graft survival without systemic immunosuppression. Diabetes 1997; 46: 317–322.
Korbutt GS, Suarez-Pinzon WL, Power RF, Rajjott RV, Rabinovitch A. Testicular sertoli cells exert both protective and destructive effects on syngeneic islet grafts in non-obese diabetic mice. Diabetologia 2000; 43(4): 474–480.
Zhang J, Ma B, Marshak-RotHSCTein A, Fine A. Characterization of a novel cis-element that regulates Fas ligand expression in corneal endothelial cells. J Biol Chem 1999; 274 (37): 26537–26542.
Korbutt GS, Elliott JF, Rajotte RV. Cotransplantation of allogeneic islets with allogeneic testicular cell aggregates allows long-term graft survival without systemic immunosuppression. Diabetes 1997; 46 (2): 317–322.
Minguela A, Marin L, Torio A, Muro M, Garcia-Alonso AM, Moya-Quiles MR, Sanchez-Bueno, Parrilla P, Alvarez-Lopez MR. CD28/CTLA4 and CD80/CD86 costimulatory molecules are mainly involved in acceptance or rejection of human liver transplant. Hum Immunol 2000; 61(7): 658–669.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. Immunogenic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000; 192 (2): 303–310.
peptides. I. Correlation of graft survival with anti-donor IgG antibody subclasses. Transplantation 1997; 64: 1665.
Bercovici N, Heurtier A, Vizler C, Pardigon N, Cambouris C, Desreumaux P, Liblau R. Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage.
Overwijk WW, Tsung A, Irvine KR, et al. gp100/pmel 17 is a murine tumor rejection antigen: induction of “self’-reactive, tumoricidal T cells using high-affinity, altered peptide ligand. J Exp Med 1998; 188 (2): 277–286.
Saborio DV, Chowdhury NC, Jin MX, Chandraker A, Sayegh MH, Oluwole SF. Regulatory T cells maintain peripheral tolerance to islet allografts induced intrathymic injection of MHC class I allopeptides.
Oluwole SF, Chodhury NC, Fawwaz RA. Induction of donor specific unresponsiveness to rat cardiac allografts by pretreatment with donor MHC class I antigen. Transplantation 1993; 55: 1396.
Liang B, Zhang Z, Inserra P, Jiang S, Lee J, Garza A, Marchalonis J, Watson R. Injection of T-cell receptor peptide reduces immunosenescence in aged C57BL/6 mice. Immunology 1998; 93:462–468.
Yuh DD, Gandy KL, Hoyt G, Reitz BA, Robbins RC. Tolerance to cardiac allografts induced in utero with fetal liver cells. Circulation 1996; 94 (9): 304–307.
Shen Z, Mohiuddin M, DiEssa VJ. Fetal inoculation with donor cells in cardiac xenotransplantation. Ann Thorac Surg 1996; 62 (5): 1360–1363
Henriksson G, Manthorpe R, Bredberg A. Antibodies to CD4 in primary Sjoreri s syndrome. Rheumatology 2000; 39 (2): 142–147.
Ando K, Fugino Y, Mochizuki. Effects of monoclonal antibodies directed at cell surface molecules on murine experimental autoimmune uveoretinitis. Graefes Arch Clin Exp Ophthalmol 1999; 237 (10): 848–854.
Honey K, Gobbold SP, Waldmann H. CD40 ligand blockade induces CD4 positive T cell tolerance and linked suppression. J Immunol 1999; 163 (9): 4805–4810.
Good RA. Progress toward production of immunologic tolerance with no or minimal toxic immunosuppression for prevention of immunodeficiency and autoimmune diseases. World J Surg 2000; 24 (7): 797–810.
Marmont AM. Stem cell transplantation for severe autoimmune diseases: progress and problems. Haematologica 1998;83(8): 733–743.
Colman PG, Steele C, Couper JJ, et al. Islet autoimmunity in infant with a type I diabetic relative is common but frequently restricted to one autoantibody.
Rhoads GG, Jackson LG, Schlesselman SE et al: The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med. 320(10):609, 1989
Mychaliska GB, Muench MO, Rice HE et al: The biology and ethics of banking fetal liver hematopoietic stem cells for in utero transplantation. J Ped Surg. 33(2):394, 1998
The Peel Report. Chairman, Sir Jonathan Peel: The use of fetuses and fetal material for research. London HMSO 1972
The Polkinghorne Report. Chairman, the Rev Dr. John Polkinghorne: Review of the guidance on the research of fetuses and fetal material. London, HMSO, 1989
Anderson F, Glasier A, Ross J, Baird DT: Attitudes of women to fetal tissue research. J Med Ethics 20(1):36, 1994
Fletcher JC: Fetal therapy, ethics and public policies. Fetal Diagn Ther 7(2):158, 1992
McCullough LB, Chervenak FA: Ethics in obstetrics and gynecology. New York, NY. Oxford, University Press, 1994
Chervenak FA, McCullough LB: Does obstetric ethics have any role in the obstetrician’s response to the abortion controversy? Am J Obstet Gynecol. 163(5 Pt 1):1425, 1990
Kingman S, Yamauchi H, Donozyski A et al: Fetal tissue research around the world. BMJ 304(6831):591, 1992
Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Ann N Y Acad Sci 850:251–269, 1998.
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Donahue, J., Carrier, E. (2002). Non-Myeloablative Transplants for Congenital Diseases. In: Bashey, A., Ball, E.D. (eds) Non-Myeloablative Allogeneic Transplantation. Cancer Treatment and Research, vol 110. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0919-6_9
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