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September 17, 1997, Vol 278, No. 11 >
ARTICLE | September 17, 1997

In Utero Hematopoietic Stem Cell Transplantation: Title and subTitle BreakA Status Report FREE

Alan W. Flake, MD; Esmail D. Zanjani, PhD
[+] Author Affiliations

Reprints: Alan W. Flake, MD, Department of Surgery, Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Room 1102D, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104 (email: flake@email.chop.edu).


JAMA. 1997;278(11):932-937. doi:10.1001/jama.1997.03550110070039
Text Size: A A A
Published online
Article
References

In utero hematopoietic stem cell transplantation is currently in its early stage of development, but it holds considerable promise as a therapeutic approach for the treatment of a large number of congenital hematologic diseases. Experimental evidence supports the concept of the early gestational fetus as a favorable recipient for cellular therapy. Unique aspects of normal hematologic and immunologic ontogeny allow engraftment and long-term persistence of transplanted hematopoietic stem cells without the requirement for myeloablation or immunosuppression. To date, 21 in utero transplants have been reported. Success has been limited to 4 fetuses, all with immunodeficiency disorders. Despite this limited evidence of clinical efficacy, interest in stem cell transplantation has been gaining momentum, and clinical application is likely to increase. Parallel advances in prenatal diagnosis, fetal intervention, and hematopoietic stem cell technology have removed many of the practical, technical, and ethical obstacles to clinical application. This progress has been accompanied by an increase in the number of centers with both the stated interest and perceived expertise to develop clinical programs. However, there is currently limited consensus among investigators on many important issues, such as the mode or timing of in utero transplantation, the ideal source or dose of donor cells, estimation of maternal and fetal risks, appropriate candidate diseases for treatment, and important ethical considerations in counseling and therapy.

REFERENCES

1 +
Billingham R, Brent L, Medawar PB.  Actively acquired tolerance of foreign cells . Nature . 1953;;172:603-606.
2 +
Owen RD.  Immunogenetic consequences of vascular anastomoses between bovine cattle twins . Science . 1945;;102:400-401.
3 +
Picus J, Aldrich W, Letvin N.  A naturally occurring bone-marrow chimeric primate . Transplantation . 1985;;39:297-303.
4 +
van Dijk B, Bommsma D, de Man A.  Blood group chimerism in human multiple births is not rare . Am J Med Genet . 1996;;61:264-268.
5 +
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 . 1979;;76:5736-5740.
6 +
Flake AW, Harrison MR, Adzick NS, Zanjani ED.  Transplantation of fetal hematopoietic stem cells in utero . Science . 1986;;233:776-778.
7 +
Harrison MR, Slotnick RN, Crombleholme TM, Golbus MS, Tarantal AF, Zanjani ED.  In-utero transplantation of fetal liver haemopoietic stem cells in monkeys . Lancet . 1989;;2:1425-1427.
8 +
Zanjani ED, Pallavicini MG, Ascensao JL, et al.  Engraftment and long-term expression of human fetal hemopoietic stem cells in sheep following transplantation in utero . J Clin Invest . 1992;;89:1178-1188.
9 +
Zanjani ED, Flake AW, Rice H, Hedrick M, Tavassoli M.  Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep . J Clin Invest . 1994;;93:1051-1055.
10 +
Linch D, Rodeck C, Nicolaldes K, et al.  Attempted bone marrow transplantation in a 17-week fetus . Lancet . 1986;;1:1382.
11 +
Touraine JL, Raudrant D, Royo C, et al.  The in-utero transplantation of stem cells in bare lymphocyte syndrome . Lancet . 1989;;1:1382.
12 +
Touraine JL.  Stem cell transplantation in primary immunodeficiency, with special reference to the first prenatal, in utero, transplants . Allergol Immunopathol (Madr) . 1991;;19:49-51.
13 +
Touraine JL, Raudrant D, Rebaud A, et al.  In utero transplantation of stem cells in humans . Bone Marrow Transplant . 1992;;1:121-126.
14 +
Slavin S, Naparstek E, Ziegler M, et al.  Clinical application of intrauterine bone marrow transplantation for treatment of genetic disease: feasibility studies . Bone Marrow Transplant . 1992;;1:189-190.
15 +
Diukman R, Golbus MS.  In utero stem cell therapy . J Reprod Med . 1992;;37:515-520.
16 +
Thilaganthan B, Nicolaides K.  Intrauterine bone-marrow transplantation at 12 weeks' gestation . Lancet . 1993;;342:243.
17 +
Cowan M, Golbus MS.  In utero hematopoietic stem cell transplants for inherited disease . Am J Pediatr Hematol Oncol . 1994;;16:35-42.
18 +
Westgren M, Ringden O, Sturla E-N, et al.  Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies . Transplantation . 1996;;61:1176-1179.
19 +
Blakemore K, Bambach H, Moser H, et al.  Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy . Am J Obstet Gynecol . 1996;;174:312. Abstract.
20 +
Flake AW, Roncarolo M-G, Puck JM, et al.  Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow . N Engl J Med . 1996;;335:1806-1810.
21 +
Wengler G, Lanfranchi A, Frusca T, et al.  Inutero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1) . Lancet . 1996;;348:1484-1487.
22 +
Haynes BF, Martin ME, Kay HH, Kurtzberg J.  Early events in human T-cell ontogeny . J Exp Med . 1988;;168:1061-1080.
23 +
Lobach DF, Hensley LL, Ho W, Haynes BF.  Human T-cell antigen expression during early stages of fetal thymic maturation . J Immunol . 1985;;135:1752-1759.
24 +
Silverstein A, Prendergast R, Kraner K.  Fetal response to antigenic stimulus, IV: rejection of skin homografts by the fetal lamb . J Exp Med . 1964;;119:955-964.
25 +
Buckley RH, Schiff SE, Schiff RI, et al.  Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency . Semin Hematol . 1993;;30:92-104.
26 +
Rice HE, Hedrick MH, Flake AW, Donegan E, Harrison MR.  Bacterial and fungal contamination of human fetal liver collected transvaginally for hematopoietic stem cell transplantation . Fetal Diagn Ther . 1993;;8:74-78.
27 +
Cefalo RC, Berghmans RL, Hall SP.  The bioethics of human fetal tissue research and therapy . Am J Obstet Gynecol . 1994;;170:12-19.
28 +
Zanjani ED, Lim G, McUlave PB, et al.  Adult haematopoietic cells transplanted to sheep fetuses continue to produce adult globins . Nature . 1982;;295:244-246.
29 +
Crombleholme TM, Harrison MR, Zanjani ED.  In utero transplantation of hematopoietic stem cells in sheep . J Pediatr Surg . 1990;;25:885-892.
30 +
Srour EF, Zanjani ED, Brandt JE, et al.  Sustained human hematopoiesis in sheep transplanted in utero during early gestation with fractionated adult human bone marrow cells . Blood . 1992;;79:1404-1412.
31 +
Srour EF, Zanjani ED, Cometta K, et al.  Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep . Blood . 1993;;82:3333-3342.
32 +
Civin CJ, Lee MJ, Hedrick M, Rice H, Zanjani ED.  Purified CD34+/lineage-/38- cells contain hematopoeitic stem cells . Blood . 1993;;82( (suppl 1) ):180A. Abstract 707.
33 +
Kawashima I, Zanjani ED, Almaida-Porada U, Flake AW, Zeng H, Ogawa M.  CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells . Blood . 1996;;87:4136-4142.
34 +
Lansdorp P, Dragowska W, Mayani H.  Ontogenyrelated changes in proliferative potential of human hematopoietic cells . J Exp Med . 1993;;178:787-791.
35 +
Zanjani ED, Flake AW, Rice H, Hendrick M, Tavassoli M.  An in-vivo comparison of potential human donor hematopoietic stem cell (HSC) sources for bone marrow transplantation using the human/sheep xenograft model . Blood . 1993;;82( (suppl 1) ):655A.
36 +
Flake AW, Zanjani ED.  Cellular therapy . In: Reece EA, ed. Fetal diagnosis and therapy. Obstet Gynecol Clin North Am . 1997;;24:159-178.
37 +
Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenberry PJ.  Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice . Blood . 1993;;81:2566-2571.
38 +
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 . 1989;;320:609-617.
39 +
Moise K.  Intrauterine transfusion with red cells and platelets . West J Med . 1993;;159:318-324.
40 +
Bowman J.  Hemolytic disease (erythroblastosis fetalis) . In: Creasy R, Resnick R, eds. Maternal-Fetal Medicine: Principles and Practice . 3rd ed. Philadelphia, Pa: WB Saunders Co; 1994;:730-733.
41 +
McKinnon S, Papadopoulos E, Carabasi M, et al.  Adoptive immunotherapy: evaluating escalating doses of donor leukocytes for relapse of CML after BMT . Blood . 1995;;86:1261-1268.
42 +
Manis J, Schwartz RS.  Agammaglobulinemia and insights into B-cell differentiation . N Engl J Med . 1996;;335:1523-1525.
43 +
Hollenbaugh D, Wu LH, Ochs HD, et al.  The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIUM1 . J Clin Invest . 1994;;94:616-622.
44 +
Andreani M, Manna M, Lucarelli U, et al.  Persistence of mixed chimerism in patients transplanted for the treatment of thalassemia . Blood . 1996;;87:3494-3499.
45 +
Walters MC, Patience M, Leisenring W, et al.  Bone marrow transplantation for sickle cell disease . N Engl J Med . 1996;;335:369-376.
46 +
Moses S.  Pathophysiology and dietary treatment of the glycogen storage diseases . J Pediatr Gastroenterol Nutr . 1990;;11:155-174.
47 +
Fletcher JC.  Fetal therapy, ethics and public policies . Fetal Diagn Ther . 1992;;7:158-168.
48 +
McCullough LB, Chervenak FA. Ethics in Obstetrics and Gynecology . New York, NY: Oxford University Press; 1994;.
49 +
Chervenak FA, McCullough LB.  Does obstetric ethics have any role in the obstetrician's response to the abortion controversy? Am J Obstet Gynecol . 1990;;163:1425-1429.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Billingham R, Brent L, Medawar PB.  Actively acquired tolerance of foreign cells . Nature . 1953;;172:603-606.
2 +
Owen RD.  Immunogenetic consequences of vascular anastomoses between bovine cattle twins . Science . 1945;;102:400-401.
3 +
Picus J, Aldrich W, Letvin N.  A naturally occurring bone-marrow chimeric primate . Transplantation . 1985;;39:297-303.
4 +
van Dijk B, Bommsma D, de Man A.  Blood group chimerism in human multiple births is not rare . Am J Med Genet . 1996;;61:264-268.
5 +
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 . 1979;;76:5736-5740.
6 +
Flake AW, Harrison MR, Adzick NS, Zanjani ED.  Transplantation of fetal hematopoietic stem cells in utero . Science . 1986;;233:776-778.
7 +
Harrison MR, Slotnick RN, Crombleholme TM, Golbus MS, Tarantal AF, Zanjani ED.  In-utero transplantation of fetal liver haemopoietic stem cells in monkeys . Lancet . 1989;;2:1425-1427.
8 +
Zanjani ED, Pallavicini MG, Ascensao JL, et al.  Engraftment and long-term expression of human fetal hemopoietic stem cells in sheep following transplantation in utero . J Clin Invest . 1992;;89:1178-1188.
9 +
Zanjani ED, Flake AW, Rice H, Hedrick M, Tavassoli M.  Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep . J Clin Invest . 1994;;93:1051-1055.
10 +
Linch D, Rodeck C, Nicolaldes K, et al.  Attempted bone marrow transplantation in a 17-week fetus . Lancet . 1986;;1:1382.
11 +
Touraine JL, Raudrant D, Royo C, et al.  The in-utero transplantation of stem cells in bare lymphocyte syndrome . Lancet . 1989;;1:1382.
12 +
Touraine JL.  Stem cell transplantation in primary immunodeficiency, with special reference to the first prenatal, in utero, transplants . Allergol Immunopathol (Madr) . 1991;;19:49-51.
13 +
Touraine JL, Raudrant D, Rebaud A, et al.  In utero transplantation of stem cells in humans . Bone Marrow Transplant . 1992;;1:121-126.
14 +
Slavin S, Naparstek E, Ziegler M, et al.  Clinical application of intrauterine bone marrow transplantation for treatment of genetic disease: feasibility studies . Bone Marrow Transplant . 1992;;1:189-190.
15 +
Diukman R, Golbus MS.  In utero stem cell therapy . J Reprod Med . 1992;;37:515-520.
16 +
Thilaganthan B, Nicolaides K.  Intrauterine bone-marrow transplantation at 12 weeks' gestation . Lancet . 1993;;342:243.
17 +
Cowan M, Golbus MS.  In utero hematopoietic stem cell transplants for inherited disease . Am J Pediatr Hematol Oncol . 1994;;16:35-42.
18 +
Westgren M, Ringden O, Sturla E-N, et al.  Lack of evidence of permanent engraftment after in utero fetal stem cell transplantation in congenital hemoglobinopathies . Transplantation . 1996;;61:1176-1179.
19 +
Blakemore K, Bambach H, Moser H, et al.  Engraftment following in utero bone marrow transplantation for globoid cell leukodystrophy . Am J Obstet Gynecol . 1996;;174:312. Abstract.
20 +
Flake AW, Roncarolo M-G, Puck JM, et al.  Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow . N Engl J Med . 1996;;335:1806-1810.
21 +
Wengler G, Lanfranchi A, Frusca T, et al.  Inutero transplantation of parental CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency (SCIDX1) . Lancet . 1996;;348:1484-1487.
22 +
Haynes BF, Martin ME, Kay HH, Kurtzberg J.  Early events in human T-cell ontogeny . J Exp Med . 1988;;168:1061-1080.
23 +
Lobach DF, Hensley LL, Ho W, Haynes BF.  Human T-cell antigen expression during early stages of fetal thymic maturation . J Immunol . 1985;;135:1752-1759.
24 +
Silverstein A, Prendergast R, Kraner K.  Fetal response to antigenic stimulus, IV: rejection of skin homografts by the fetal lamb . J Exp Med . 1964;;119:955-964.
25 +
Buckley RH, Schiff SE, Schiff RI, et al.  Haploidentical bone marrow stem cell transplantation in human severe combined immunodeficiency . Semin Hematol . 1993;;30:92-104.
26 +
Rice HE, Hedrick MH, Flake AW, Donegan E, Harrison MR.  Bacterial and fungal contamination of human fetal liver collected transvaginally for hematopoietic stem cell transplantation . Fetal Diagn Ther . 1993;;8:74-78.
27 +
Cefalo RC, Berghmans RL, Hall SP.  The bioethics of human fetal tissue research and therapy . Am J Obstet Gynecol . 1994;;170:12-19.
28 +
Zanjani ED, Lim G, McUlave PB, et al.  Adult haematopoietic cells transplanted to sheep fetuses continue to produce adult globins . Nature . 1982;;295:244-246.
29 +
Crombleholme TM, Harrison MR, Zanjani ED.  In utero transplantation of hematopoietic stem cells in sheep . J Pediatr Surg . 1990;;25:885-892.
30 +
Srour EF, Zanjani ED, Brandt JE, et al.  Sustained human hematopoiesis in sheep transplanted in utero during early gestation with fractionated adult human bone marrow cells . Blood . 1992;;79:1404-1412.
31 +
Srour EF, Zanjani ED, Cometta K, et al.  Persistence of human multilineage, self-renewing lymphohematopoietic stem cells in chimeric sheep . Blood . 1993;;82:3333-3342.
32 +
Civin CJ, Lee MJ, Hedrick M, Rice H, Zanjani ED.  Purified CD34+/lineage-/38- cells contain hematopoeitic stem cells . Blood . 1993;;82( (suppl 1) ):180A. Abstract 707.
33 +
Kawashima I, Zanjani ED, Almaida-Porada U, Flake AW, Zeng H, Ogawa M.  CD34+ human marrow cells that express low levels of Kit protein are enriched for long-term marrow-engrafting cells . Blood . 1996;;87:4136-4142.
34 +
Lansdorp P, Dragowska W, Mayani H.  Ontogenyrelated changes in proliferative potential of human hematopoietic cells . J Exp Med . 1993;;178:787-791.
35 +
Zanjani ED, Flake AW, Rice H, Hendrick M, Tavassoli M.  An in-vivo comparison of potential human donor hematopoietic stem cell (HSC) sources for bone marrow transplantation using the human/sheep xenograft model . Blood . 1993;;82( (suppl 1) ):655A.
36 +
Flake AW, Zanjani ED.  Cellular therapy . In: Reece EA, ed. Fetal diagnosis and therapy. Obstet Gynecol Clin North Am . 1997;;24:159-178.
37 +
Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenberry PJ.  Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice . Blood . 1993;;81:2566-2571.
38 +
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 . 1989;;320:609-617.
39 +
Moise K.  Intrauterine transfusion with red cells and platelets . West J Med . 1993;;159:318-324.
40 +
Bowman J.  Hemolytic disease (erythroblastosis fetalis) . In: Creasy R, Resnick R, eds. Maternal-Fetal Medicine: Principles and Practice . 3rd ed. Philadelphia, Pa: WB Saunders Co; 1994;:730-733.
41 +
McKinnon S, Papadopoulos E, Carabasi M, et al.  Adoptive immunotherapy: evaluating escalating doses of donor leukocytes for relapse of CML after BMT . Blood . 1995;;86:1261-1268.
42 +
Manis J, Schwartz RS.  Agammaglobulinemia and insights into B-cell differentiation . N Engl J Med . 1996;;335:1523-1525.
43 +
Hollenbaugh D, Wu LH, Ochs HD, et al.  The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIUM1 . J Clin Invest . 1994;;94:616-622.
44 +
Andreani M, Manna M, Lucarelli U, et al.  Persistence of mixed chimerism in patients transplanted for the treatment of thalassemia . Blood . 1996;;87:3494-3499.
45 +
Walters MC, Patience M, Leisenring W, et al.  Bone marrow transplantation for sickle cell disease . N Engl J Med . 1996;;335:369-376.
46 +
Moses S.  Pathophysiology and dietary treatment of the glycogen storage diseases . J Pediatr Gastroenterol Nutr . 1990;;11:155-174.
47 +
Fletcher JC.  Fetal therapy, ethics and public policies . Fetal Diagn Ther . 1992;;7:158-168.
48 +
McCullough LB, Chervenak FA. Ethics in Obstetrics and Gynecology . New York, NY: Oxford University Press; 1994;.
49 +
Chervenak FA, McCullough LB.  Does obstetric ethics have any role in the obstetrician's response to the abortion controversy? Am J Obstet Gynecol . 1990;;163:1425-1429.

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