Mixed Lymphocyte Culture of Human Fetal Liver Cells

Lindton, Bim; Markling, L; Ringdén, Olle; Kjældgaard, A.; Gustafson, Owe; Westgren, Magnus

doi:10.1159/000020979

Cited by 30 publications

(17 citation statements)

References 19 publications

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“…We have found that FLCs can respond in MLC to a varying degree from the eighth gestational week. 24 However, since fMSCs suppress the proliferation induced by mitogens, it appears that they, at least possess some of the immunomodulatory properties found in aMSC. To conclude, fMSCs were successfully grown in culture.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells

Götherström

Ringdén

Westgren

et al. 2003

Bone Marrow Transplant

185

126

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Summary:Adult mesenchymal stem cells (MSCs) have been suggested to decrease lymphocyte proliferation in vitro. We hypothesised that foetal MSCs (fMSCs) would have an immunosuppressive effect on allograft responses in vitro. Human MSCs were isolated and cultured from firsttrimester foetal livers and characterised by flow cytometry. fMSC stained positive for CD29, CD44, CD166, CD105, SH-3 and SH-4, and negative for CD14, CD34 and CD45. When plated on adipogenic, chondrogenic and osteogenic media, fMSC differentiated into the respective cell lineage. Compared to adult MSC (aMSC), the proliferative capacity of fMSC was higher. Mitogen stimulation of PBL was inhibited by fMSC. The greatest inhibition (78%) was seen when 30 000 fMSCs were added to 150 000 lymphocytes stimulated by phytohaemagglutinin. Adult and fMSCs were added to mixed lymphocyte cultures (MLC) containing peripheral blood lymphocytes or foetal liver cells. Unlike aMSC, fMSCs did not inhibit MLC. fMSC could be culture-expanded several million folds with no loss of phenotype characteristics, which makes them ideal for ex vivo expansion. fMSC inhibit lymphocyte proliferation induced by mitogens, but not alloreactivity as measured by MLC.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells

Götherström

Ringdén

Westgren

et al. 2003

Bone Marrow Transplant

185

126

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“…In the human fetus, intrauterine death also occurred from "overwhelming engraftment" [31] when the T-cell dose exceeded 10 8 /kg. While the fetus has been assumed to be "preimmune" [32,33], it is probably more correct to term the fetus "early immune," as immunocompetent cells are present very early in the fetus, suggesting that it is not truly devoid of immune function [34][35][36][37][38][39][40][41]. If one assumes that the fetus has some immune function, it is not surprising that a relatively large number of donor T cells are needed to ensure successful engraftment, presumably through a donor-versus-host effect.…”

Section: Discussionmentioning

confidence: 99%

In Utero Hematopoietic Stem Cell Transplantation in Nonhuman Primates: The Role of T Cells

et al. 2003

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In utero transplantation of hematopoietic stem cells is a promising treatment for immune and hematologic diseases of fetuses and newborns. Unfortunately, there are limited data from nonhuman primates and humans describing optimal transplantation conditions. The purpose of this investigation was to determine the effect of T-cell number on engraftment and the level of chimerism after in utero transplantation in nonhuman primates. CD34 + allogeneic adult bone marrow cells, obtained from the sire after G-CSF and stem cell factor administration, were transplanted into female fetal recipients. The average CD34 + cell dose was 3.0 × × 10 9 /kg (range, 9.9 × × 10 8 to 4.4 × × 10 9 ) and the T-cell dose ranged from 2.6 × × 10 5 to 1.1 × × 10 8 /kg. Chimerism was determined in peripheral blood subsets (CD2, CD13, and CD20) and in progenitor cell populations by using polymerase chain reaction. Chimerism was noted in seven of eight live-born animals. The level of chimerism in the progenitor population was related to the fetal T-cell dose (r = 0.64, p < 0.02). At the lowest T-cell dose (2.6 × × 10 5 /kg), no chimerism was detected. As the T-cell dose increased to 10 6-7 /kg, the level of chimerism increased. Adjusting the T-cell dose to 1.1 × × 10 8 /kg resulted in fatal graft-versus-host disease (GVHD). The results of this study emphasize the importance of T cells in facilitating donor cell engraftment and in producing GVHD in fetal nonhuman primates. Some animals achieved levels of chimerism in the marrow hematopoietic progenitor cell population that would likely have clinical relevance. However, the levels of chimerism in peripheral blood were too low for therapeutic benefit. Further studies are needed to test methods that are likely to enhance donor cell engraftment and peripheral blood levels of donor cells.

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“…2,8 Moreover, T cells showing TCR rearrangement have been observed in human FL in the 13th week of gestation, 26 and FL NK cells and fetal T cells have been demonstrated alloreactive in vitro. [27][28][29] These lines of evidence could indicate the engraftment failure of FL hematopoietic cells transplanted in utero in allogeneic recipients. 30,31 Recent studies suggest that an immunoreaction takes place when the fetus is exposed to allogeneic cells.…”

Section: Discussionmentioning

confidence: 99%

Immunoresponse against the transgene limits hematopoietic engraftment of mice transplanted in utero with virally transduced fetal liver

et al. 2010

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In utero cell and gene therapies constitute alternative strategies to the postnatal treatment of inherited diseases. Fetal hematopoietic progenitors could be a potential source of donor cells for these strategies. In this study, hematopoietic lineage-negative fetal liver cells from 14.5-day-old fetuses were transduced under different cytokine and culture combinations using a lentiviral vector expressing the enhanced green fluorescent protein (EGFP). When cells were transduced for 6 h in the presence of mSCF, hTPO and FLT3-L in retronectin-coated dishes at a multiplicity of infection of 10 transduction units/cell, up to 70% of granulo-macrophage colony-forming cells expressed the EGFP reporter gene. In utero transplantation experiments revealed that conditions leading to high transduction efficiencies were associated with poor engraftments of syngeneic recipients. Significantly, this effect was associated with the detection of a humoral and cellular immunoresponse against the transgenic protein. Moreover, the humoral response against EGFP was detected not only in in utero transplanted recipients but also in the operated mothers, suggesting the maternal origin of the anti-EGFP immunoresponse. These observations reinforce the necessity of carefully studying the potential immunoresponses in future prenatal gene therapy protocols.

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Mixed Lymphocyte Culture of Human Fetal Liver Cells

Cited by 30 publications

References 19 publications

Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells

Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells

In Utero Hematopoietic Stem Cell Transplantation in Nonhuman Primates: The Role of T Cells

Immunoresponse against the transgene limits hematopoietic engraftment of mice transplanted in utero with virally transduced fetal liver

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