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

Shields, Laurence E.; Gaur, Lakshmi K.; Gough, Mike; Potter, Jennifer; Sieverkropp, Aimee; Andrews, Robert G.

doi:10.1634/stemcells.21-3-304

Cited by 55 publications

(54 citation statements)

References 46 publications

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“…Subsets of T cells within the donor BM inoculum are known to provide important engraftment-facilitating properties. 10,18,44,45 CD26 is expressed at low density on T cells with markedly enhanced expression after T-cell activation. CD26 plays an important role in T-cell activation and has been shown to be a receptor capable of generating T-cell costimulatory signals.…”

Section: Discussionmentioning

confidence: 99%

CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

Peranteau

Endo

Adibe

et al. 2006

Blood

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In utero hematopoietic-cell transplantation (IUHCT) can induce donor-specific tolerance to facilitate postnatal transplantation. Induction of tolerance requires a threshold level of mixed hematopoietic chimerism. CD26 is a peptidase whose inhibition increases homing and engraftment of hematopoietic cells in postnatal transplantation. We hypothesized that CD26 inhibition would increase donorcell homing to the fetal liver (FL) and improve allogeneic engraftment following IUHCT. To evaluate this hypothesis, B6GFP bone marrow (BM) or enriched hematopoietic stem cells (HSCs) were transplanted into allogeneic fetal mice with or without CD26 inhibition. Recipients were analyzed for FL homing and peripheral-blood chimerism from 4 to 28 weeks of life. We found that CD26 inhibition of donor cells results in ( IntroductionIn utero hematopoietic-cell transplantation (IUHCT) has the potential to treat many congenital hematologic and genetic disorders. 1,2 It is a nonmyeloablative approach that can, under some circumstances, achieve mixed allogeneic chimerism and associated donorspecific tolerance. [3][4][5][6] This tolerance can facilitate postnatal cellular or organ transplantations with minimal or no myeloablative or immunosuppressive conditioning. 3,4,[6][7][8][9][10][11][12][13][14][15] Although engraftment of allogeneic or xenogeneic cells has been achieved, the levels of donor-cell chimerism in most circumstances following IUHCT alone have been below what would be considered therapeutic for most target diseases. [3][4][5][6][7][16][17][18][19][20][21] Additionally, the frequency of engraftment following IUHCT of allogeneic or xenogeneic cells has also been relatively low. 3,[17][18][19]21 Thus, the ideal goal of a single in utero transplantation resulting in therapeutic levels of engraftment or a 100% frequency of donor-specific tolerance has been elusive. A significant barrier to allogeneic engraftment following IUHCT is limited space in the fetus due to host-cell competition from a robust and highly proliferative fetal hematopoeitic compartment. 22 This has been supported by the presence of high-level engraftment after IUHCT in circumstances where a competitive or survival advantage exists for donor cells. [23][24][25][26][27][28] Additionally, the inability of hematopoietic stem cells (HSCs) to home and engraft with absolute efficiency may limit donor-cell engraftment following allogeneic IUHCT. 29 Thus, strategies that selectively increase donor HSC homing and engraftment in the fetal recipient may increase both the levels and frequency of engraftment following allogeneic IUHCT.CD26/dipeptidylpeptidase IV is a membrane-bound ectopeptidase that is expressed on a subset of HSCs and early hematopoietic progenitor cells. 30,31 It cleaves dipeptides from the N terminus of polypeptide chains that contain the N-terminal X-Pro or X-Ala motif. 30,32 Among its many substrates, CD26 has been shown to have selectivity for stromal-cell-derived factor 1␣ (SDF-1␣)/CXCL12. 33 SDF-1␣ is a chemokine present at high levels in adult ...

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Section: Discussionmentioning

confidence: 99%

CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

Peranteau

Endo

Adibe

et al. 2006

Blood

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“…Another potential explanation is that cytokine exposure of the donor marrow leads to expansion of immunoregulatory cell populations capable of facilitating engraftment in an allogeneic microenvironment [10,58,59]. However, as shown in Figure 3 and Table 2, a lineage analysis of the cultured cells revealed a nearly identical phenotype between the cell groups and specifically no differences in the frequencies of CD4 + CD25 + or CD3 + DX5 + cells.…”

Section: Discussionmentioning

confidence: 99%

“…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 nonhuman primate models of IUHCT [3,[9][10][11][12][13]. These levels are too low for correction of most diseases and have not been demonstrated to reliably induce tolerance.…”

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confidence: 99%

“…While recent success in the swine model is encouraging, a better characterization of swine immunology and hematopoietic ontogeny is needed to reconcile the results of these experiments with clinical and nonhuman primate studies [14,15]. Lastly, protocols designed to enhance chimerism, such as postnatal boosting after irradiation or donor lymphocyte infusion [16,17], require the presence of tolerance and have not been successful in non-human primates [9,10].…”

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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 the absence of immunosuppression, only microchimerism has been achieved in human fetal recipients or nonhuman primate models of IUHCT. [1][2][3][4][5][6] These levels are too low for the correction of most diseases and have not been demonstrated to predict tolerance. The reasons for this failure are unclear and reflect a limited understanding of the engraftment barriers involved in clinical IUHCT.…”

Section: Introductionmentioning

confidence: 99%

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

Durkin

Jones

Rajesh

et al. 2008

Blood

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The failure of engraftment in human cases of in utero hematopoietic cell transplantation (IUHCT) in which no immunodeficiency exists suggests the presence of an unrecognized fetal immune barrier. A similar barrier in murine IUHCT appears to be dependent on the chimerism level and is poorly explained by a lack of T-cell tolerance induction. Therefore, we studied the effect of the chimerism level on engraftment and host natural killer (NK)-cell education in a murine model of IUHCT. The dose of transplanted cells was found to exhibit a strong correlation with both the engraftment rate and chimerism level. More specifically, a threshold level of initial chimerism (> 1.8%) was identified that predicted durable engraftment for allogeneic IUHCT, whereas low initial chimerism (< 1.8%) predicted a loss of engraftment. NK cells taken from chimeras above the "chimerism threshold" dis-

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

Cited by 55 publications

References 46 publications

CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

CD26 inhibition enhances allogeneic donor-cell homing and engraftment after in utero hematopoietic-cell transplantation

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

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

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