Alloreactivity following in utero transplantation of cytokine-stimulated hematopoietic stem cells

Sefrioui, Hassan; Donahue, Jody; Srivastava, Anand; Gilpin, Elizabeth A.; Lee, Tzong‐Hae; Carrier, Ewa

doi:10.1016/s0301-472x(02)00803-2

Cited by 18 publications

(24 citation statements)

References 38 publications

(65 reference statements)

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“…We have previously demonstrated that prenatal immunization can be induced with cytokine-stimulated allogeneic stem cells (9,10). We have shown that, in tolerant mice, donor chimerism can be increased by postnatal boosts (transplants with corresponding donor cells) (11), whereas in immunized mice, postnatal boosts lead to rapid decline of donor chimerism (12).…”

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confidence: 99%

Chimerism and Tolerance Post-In Utero Transplantation with Embryonic Stem Cells

et al. 2004

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Chimerism and Tolerance Post-In Utero Transplantation with Embryonic Stem Cells

et al. 2004

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“…In previous studies by Sefrioui et al [64], SCF and granulocyte colony-stimulating factor were used to mobilize donor HSCs in adult mice. The Sca-1 + Lin − mobilized B6 HSCs were then enriched from the donor spleen and prenatally transplanted into 13 dpc Balb/c fetal recipients [64].…”

Section: Discussionmentioning

confidence: 99%

“…The Sca-1 + Lin − mobilized B6 HSCs were then enriched from the donor spleen and prenatally transplanted into 13 dpc Balb/c fetal recipients [64]. Transplanted Balb/c recipients demonstrated no evidence for tolerance at 4 and 6 months of age.…”

Section: Discussionmentioning

confidence: 99%

Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment

Shaaban

Kim

Gaur

et al. 2006

Experimental Hematology

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Objective-In the absence of immunodeficiency, only microchimerism (<0.1%) has been achieved in human fetal recipients or nonhuman primates following in utero hematopoietic cell transplantation (IUHCT). We hypothesized that enhanced long-term engraftment might be more reliably achieved in microchimeric systems if higher levels of chimerism existed during development of adaptive immunity. To evaluate this hypothesis, we stimulated the donor cells with vascular endothelial growth factor (VEGF) and stem cell factor (SCF) prior to IUHCT in a chimerism-resistant murine strain combination. Methods-DonorBalb/c marrow was cultured in media with or without VEGF and SCF supplementation for 12 hours prior to IUHCT into B6 fetuses at 14 days postcoitum (dpc). Donor cell phenotype, homing, and chimerism were assessed at short and long-term time points and transplanted animals received skin allografts at 8 weeks.Results-In pretreated allogeneic recipients, early chimerism rates were more than double that of controls (71% vs 33%, p = 0.01). These differences were associated with higher numbers of pretransplant donor cell colony-forming cells without change in donor cell homing. Despite prolonged skin allograft survival for pretreated recipients compared with controls (mean survival = 20.8 vs 8.2 days, p < 0.001), long-term engraftment was unchanged.Conclusions-These findings demonstrate that higher levels of early chimerism in recipients of cytokine-stimulated marrow result in improved short-term chimerism and tolerance. Future studies are needed to confirm the existence of a "threshold" level of chimerism necessary to sustain longterm engraftment.In utero hematopoietic cell transplantation (IUHCT) is a promising approach for treatment of a variety of genetic disorders without the need for immunosuppression [1][2][3][4][5][6]. IUHCT has been successfully applied clinically in the treatment of fetuses with prenatally diagnosed Xlinked severe combined immunodeficiency disease [5,7,8], but has not been successful for treatment of other congenital diseases. In the absence of immunosuppression, either no engraftment or only microchimerism (<0.1%) has been achieved in human fetal recipients or Similar observations have been made in "chimerism-resistant" murine strain combinations, where even long-term microchimerism has been difficult to achieve with clinically relevant doses of marrow. We have previously shown that durable donor-specific tolerance across major histocompatibility complex (MHC) barriers can be achieved by the mechanism of central thymic deletion when adequate levels of chimerism are present [16][17][18][19]. Therefore, we hypothesized that tolerance and long-term engraftment might be more reliably achieved in microchimeric systems by enhancing the levels of prenatal chimerism during development of adaptive immunity. One clinically relevant way to enhance chimerism is by ex vivo stimulation of the donor cells with cytokines that impart a competitive advantage for the homing and engraftment of the transplanted c...

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“…In this report, we provide evidence that fetal lymphocytes obtained during the middle of the second trimester were capable of responding in primary mixed lymphocyte cultures to haploidentical targets. It has been shown in murine models that alloreactivity was induced in utero against transplanted cells, with little to no engraftment in MHC-mismatched hosts [19,20] . Nonetheless, following intrauterine transplantation of paternal stem cells at 13, 19 and 24 weeks of gestation for the treatment of ␣ -thalassemia, donor tolerance was induced in the absence of signifi cant engraftment [21] .…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in Fetal Immunocompetence during the Second Trimester of Gestation

Tse

Ching²,

Yousefzadeh³

et al. 2005

Fetal Diagn Ther

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Objective: To address the role that alloreactivity may play and better define the window for histoincompatible stem cell transplantation in utero. Subjects, Material and Methods: We studied 9 fetal blood specimens obtained by cardiocentesis during elective abortions in the second trimester by multicolor flow cytometry and in vitro stimulation. Results: Lymphocytes ranged from adult levels (3/9) to >90% leukocytes. Six specimens had T cells within adult range. T cells in the other specimens were reduced, while B cells were conversely elevated. This variability did not correlate with gestational age, or leukocyte composition. Following 4 h of mitogenesis, fetal CD4+ and CD8+ T cells from 1 of 5 specimens showed a response similar to that of maternal T cells, while the other 4 specimens showed a diminished response (0.3 ± 0.2-fold). This heterogeneity did not correlate with gestational age, or lymphocyte subset distribution. Following 18 h of in vitro mitogenesis, fetal T cells from 2 specimens showed a response similar to that of maternal T cells (0.8 ± 0.2-fold). Despite that, one specimen gave a 3-fold greater response in a one-way mixed lymphocyte reaction vs. maternal cells compared to the other specimen. Conclusion: We determine that fetal immunocompetence differs greatly during the second trimester and assessment of host vs. donor reactivity prior to in utero transplantation is likely to potentiate more favorable outcomes.

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Alloreactivity following in utero transplantation of cytokine-stimulated hematopoietic stem cells

Cited by 18 publications

References 38 publications

Chimerism and Tolerance Post-In Utero Transplantation with Embryonic Stem Cells

Chimerism and Tolerance Post-In Utero Transplantation with Embryonic Stem Cells

Prenatal transplantation of cytokine-stimulated marrow improves early chimerism in a resistant strain combination but results in poor long-term engraftment

Heterogeneity in Fetal Immunocompetence during the Second Trimester of Gestation

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