Bone‐Marrow and Fetal‐Liver Transplantation in Immunodeficiencies and Inborn Errors of Metabolism: Lack of Significant Restriction of T‐Cell Function in Long‐Term Chimeras Despite HLA‐Mismatch

Touraine, Jean‐Louis

doi:10.1111/j.1600-065x.1983.tb01070.x

Cited by 54 publications

(32 citation statements)

References 23 publications

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“…The subject presented a normal defence against pathogenic microorganisms such as fungi, bacteria, and viruses. In addition, he was found to mount a subnormal to normal in vivo Ab response after vaccination with a variety of viral and bacterial Ag including TT (1,9).…”

Section: Discussionmentioning

confidence: 99%

“…Severe combined immunodeficiency (SCID)' can be treated by bone marrow transplantation (1). As an alternative, especially when no histocompatible marrow donor is available, fetal liver and thymus transplantation (FLTT) can be successfully em-ployed (1).…”

Section: Introductionmentioning

confidence: 99%

“…As an alternative, especially when no histocompatible marrow donor is available, fetal liver and thymus transplantation (FLTT) can be successfully em-ployed (1). In (2).…”

Section: Introductionmentioning

confidence: 99%

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Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody.

1986

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Fetal liver and thymus transplantation can be successfully employed for the treatment of severe combined immunodeficiency disease. In virtually all cases, donor and recipient cells are HLA mismatched. In a patient suffering from a severe combined immunodeficiency disease, full immunological reconstitution was obtained after fetal liver and thymus transplantation. HLA typing revealed that the patient's T cells were of donor origin, while the B cells and monocytes were of host origin. Despite this complete HLA mismatch, the patient was found to mount a subnormal to normal antibody response in vivo. This finding is in contrast with the concept that antigen recognition by T cells is major histocompatibility complex (MHC) restricted. To define the mechanism responsible for this in vivo antibody response, antibody production by peripheral blood mononuclear cells from the patient was tested in vitro after in vivo booster. The in vitro anti-tetanus toxoid antibody production was similar to that of the control group. In addition, specific proliferative responses to tetanus toxoid were obtained. Immunoglobulin allotype determination showed that antibodies were synthetized by host B cells. The results of the present study indicate that transplanted T lymphocytes and recipient cells cooperate despite complete HLA mismatch.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody.

1986

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“…Accumulated evidence suggests that fetal liver (FL) or umbilical cord blood (CB) or both represent alternative and possibly more "universal" sources of "early" HSCs and possess a better proliferative potential and also a preimmune status that may be important in mismatched transplantation situations. [3][4][5][6][7] However, both sources are compromised by the relatively small number of cells available. Therefore, the future clinical potential of FL and CB would be strongly enhanced if methods allowing a reliable HSC expansion, perhaps to a degree as little as 20-to 100-fold, without a loss of their engraftment ability, could be developed.…”

Section: Introductionmentioning

confidence: 99%

Long-term expansion of transplantable human fetal liver hematopoietic stem cells

Rollini

Kaiser

Hull

et al. 2004

Blood

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IntroductionThere is a growing clinical need for large numbers of human hematopoietic stem cells (HSCs) for transplantation or gene therapy. 1,2 In cancer patients in whom the probability of tumor cell contamination in either leukapheresis or bone marrow (BM) is high, the use of allogeneic cells is preferable. Accumulated evidence suggests that fetal liver (FL) or umbilical cord blood (CB) or both represent alternative and possibly more "universal" sources of "early" HSCs and possess a better proliferative potential and also a preimmune status that may be important in mismatched transplantation situations. 3-7 However, both sources are compromised by the relatively small number of cells available. Therefore, the future clinical potential of FL and CB would be strongly enhanced if methods allowing a reliable HSC expansion, perhaps to a degree as little as 20-to 100-fold, without a loss of their engraftment ability, could be developed. 8 Ex vivo expansion of CB and of adult nonobese diabetic/severe combined immunodeficiency (NOD/SCID)-repopulating cells (SRCs; Wang et al 9 ) has been demonstrated (eg, Piacibello et al 10 and Gammaitoni et al 11 ), but successful expansion of FL SRCs has not been reported so far.We recently published a simple and reproducible stroma-free liquid culture system allowing long-term (Ͼ 6 months) expansion of human hematopoietic cells contained within previously frozen crude FL cell suspensions. In these cultures, CD34 ϩ cells, primitive colony-forming progenitors, and cells possessing a putative stem cell phenotype were not only present, they also underwent a continuous amplification. 12 However, the maintenance and expansion of functional repopulating HSCs was not tested. This is critical given the dissociation between stem cell phenotype and in vivo repopulating function observed in hematopoietic cultures. [13][14][15] Here, we used the NOD/SCID mouse xenotransplantation assay to quantify FL SRCs and demonstrated that our culture conditions allowed a 10-to over 100-fold net SRC expansion following 28 days of culture. Study designCryopreserved human FL crude cellular suspensions were prepared from aborted fetuses (gestational weeks 12-17) as described, with the approval of the ethical committee of the Lausanne University Medical Faculty. 12,16 Total nucleated FL hematopoietic cells were expanded in RPMI 1640 supplemented with 8% human AB plasma, Flt-3 ligand (50 ng/mL), interleukin 6 (10 ng/mL), megakaryocyte growth and development factor (MGDF; 10 ng/mL), and stem cell factor (SCF; 50 ng/mL). Cultures were fed and maintained as described, 12 except that cells were grown in T25 flasks instead of 24-well plates. For NOD/SCID-repopulating assays, 6-to 8-week old NOD/LtSz-scid/scid (NOD/SCID) mice were sublethally irradiated (375 cGy using a 137 Cs source), and cells to be tested (at the doses indicated, in about 600 L RPMI) were injected into the lateral tail vein 4 to 24 hours later. Mice were killed after 6, 8, or 12 weeks, the BM harvested from femora, and human engraftment analyzed b...

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“…In the fourth case, the fetus is alive and well and birth is expected soon. In utero transplantation of stem cells is a therapy with remark able advantages: (a) tolerance induction due to the immune immaturity of the host, (b) lack of graft-versus-host disease due to the immaturity of the donor, (c) ideal isolation of the fetus in the maternal uterus, and (d) an optimal envi ronment for donor fetal cell development in the vicinity of host fetal cells and growth factors.Transplantation of fetal liver stem cells results in hemopoietic and lymphopoietic reconstitution [1][2][3]. Due to immaturity of the lymphoid system of the fetal donor (especially the absence of T lymphocytes) in the early ontogenetic phase, no or mild graft-versus-host reaction (GvHR) develops, provided that the donor age is below 13 weeks postfertilization.…”

mentioning

confidence: 99%

Treatment of Human Fetuses and Induction of Immunological Tolerance in Humans by in utero Transplantation of Stem Cells into Fetal Recipients

Touraine¹

1996

Acta Haematol

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Since 1976, we have performed more than 240 fetal tissue transplants (FLTs) to treat 63 patients with severe immunodeficiency disease (IDD), with inborn errors of metabolism (IEM), or with severe aplastic anemia. In both IDD and IEM, FLT into postnatal recipients has demonstrated beneficial effects (67% of the patients were either cured or improved significantly). In 1988, we developed in utero FLT into human fetuses, taking advantage of the immunological tolerance of young fetuses. The transplants have involved fetuses suffering from various diseases at 12-28 weeks postfertilization with 2 of the 6 cases eventually resulting in abortion. With the 4 other fetuses, a favorable outcome was observed: 3 children are now more than 4 years old, and are alive and well with evidence of engraftment, reconstitution of immunity, and partial correction of β° thalassemia. In the fourth case, the fetus is alive and well and birth is expected soon. In utero transplantation of stem cells is a therapy with remarkable advantages: (a) tolerance induction due to the immune immaturity of the host, (b) lack of graft-versus-host disease due to the immaturity of the donor, (c) ideal isolation of the fetus in the maternal uterus, and (d) an optimal environment for donor fetal cell development in the vicinity of host fetal cells and growth factors.

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Bone‐Marrow and Fetal‐Liver Transplantation in Immunodeficiencies and Inborn Errors of Metabolism: Lack of Significant Restriction of T‐Cell Function in Long‐Term Chimeras Despite HLA‐Mismatch

Cited by 54 publications

References 23 publications

Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody.

Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody.

Long-term expansion of transplantable human fetal liver hematopoietic stem cells

Treatment of Human Fetuses and Induction of Immunological Tolerance in Humans by in utero Transplantation of Stem Cells into Fetal Recipients

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