Post-transcriptional (re)programming of B lymphocyte development: From bench to bedside?

Hematopoiesis, a process which generates blood and immune cells, changes significantly during mammalian development. Definitive hematopoiesis is marked by the emergence of long-term hematopoietic stem cells (HSCs). Here, we will focus on the post-transcriptional differences between fetal liver (FL) and adult bone marrow (ABM) HSCs. It remains unclear how or why exactly FL HSCs transition to ABM HSCs, but we aim to leverage their differences to revive an old idea: in utero HSC transplantation. Unexpectedly, the expression of certain RNA-binding proteins (RBPs) play an important role in HSC specification, and can be employed to convert or reprogram adult HSCs back to a fetal-like state. Among other features, FL HSCs have a broad differentiation capacity that includes the ability to regenerate both conventional B and T cells, as well as innate-like or unconventional lymphocytes such as B-1a and marginal zone B (MzB) cells. This chapter will focus on RNA binding proteins, namely LIN28B and IGF2BP3, that are expressed during fetal life and how they promote B-1a cell development. Furthermore, this chapter considers a potential clinical application of synthetic co-expression of LIN28B and IGF2BP3 in HSCs.

Maternal Administration of Busulfan before in Utero Hematopoietic Cell Transplantation Improves Congenic Bone Marrow Cell Engraftment in a Murine Model.

In utero hematopoietic cell transplantation (IUHCT) is a nonmyeloablative procedure that leads to donor cell chimerism and donor-specific tolerance. However, most clinical applications of IUHCT have failed because of low levels or even no engraftment of donor cells in immunologically normal fetuses. It is likely that the competition from the host hematopoietic compartment is the primary barrier to successful IUHCT, suggesting that conditioning methods that provide a competitive advantage to donor cells may lead to higher-level engraftment following IUHCT. This study aimed to research whether maternal administration of low-dose total body irradiation (TBI) or busulfan (BU) before IUHCT may result in increased donor cell chimerism in postnatal bone marrow transplantation in a congenic murine model. We first determined the birth and mortality rates after maternal administration of low-dose TBI (0, 2 or 4 Gy) or BU (5, 10, 15, or 20 mg/kg) before IUHCT in B6 mice. The mice that received 2 Gy TBI plus IUHCT showed significantly lower birth rate (23.3%) and a 100% 3-day mortality rate. The mice that received 10 mg/kg BU plus IUHCT had similar birth and 3-day mortality rates (58.6% and 0%) compared to mice that received IUHCT alone (61.1% and 4.55%). We then performed maternal administration of BU at 1 of 3 dosages (5, 10, or 15 mg/kg) at 24 hours before intrauterine transplantation of 2.5 × 105 B6GFP Sca-1+ bone marrow cells (BMCs) or 2.5 × 106 B6GFP BMCs on gestational day 14 (E14). Green fluorescent protein (GFP) chimerism in peripheral blood mononuclear cells (PBMCs), RBCs, and platelets of mice at 4 weeks of age was enhanced significantly with an increase in BU dose. Moreover, GFP chimerism of PBMCs from the B6GFP BMC group was significantly higher than that of the B6GFP Sca-1+ BMC group (22.56% versus 7.20%; P = .018). Finally, the pregnant mice were treated with 10 mg/kg of BU at E13, E14, or E15, followed by intrauterine transplantation of 2.5 × 106 B6GFP BMCs 24 hours later. Except for the short-term level of chimerism in PBMCs, which showed no significant difference among the 3 study groups, the results indicate that both short-term (age 4 weeks) and long-term (age 14 weeks) engraftment in PBMCs, RBCs, and platelets was higher in group E16 compared with groups E14 and E15. We also discovered that the engraftment was stable, multilineage, and increased with time. In conclusion, maternal administration of BU, but not of TBI, along with IUHCT could significantly enhance engraftment in a congenic murine model.

In Utero Cell Treatment of Hemophilia A Mice via Human Amniotic Fluid Mesenchymal Stromal Cell Engraftment.

Hemophilia is a genetic disorder linked to the sex chromosomes, resulting in impaired blood clotting due to insufficient intrinsic coagulation factors. There are approximately one million individuals worldwide with hemophilia, with hemophilia A being the most prevalent form. The current treatment for hemophilia A involves the administration of clotting factor VIII (FVIII) through regular and costly injections, which only provide temporary relief and pose inconveniences to patients. In utero transplantation (IUT) is an innovative method for addressing genetic disorders, taking advantage of the underdeveloped immune system of the fetus. This allows mesenchymal stromal cells to play a role in fetal development and potentially correct genetic abnormalities. The objective of this study was to assess the potential recovery of coagulation disorders in FVIII knockout hemophilia A mice through the administration of human amniotic fluid mesenchymal stromal cells (hAFMSCs) via IUT at the D14.5 fetal stage. The findings revealed that the transplanted human cells exhibited fusion with the recipient liver, with a ratio of approximately one human cell per 10,000 mouse cells and produced human FVIII protein in the livers of IUT-treated mice. Hemophilia A pups born to IUT recipients demonstrated substantial improvement in their coagulation issues from birth throughout the growth period of up to 12 weeks of age. Moreover, FVIII activity reached its peak at 6 weeks of age, while the levels of FVIII inhibitors remained relatively low during the 12-week testing period in mice with hemophilia. In conclusion, the results indicated that prenatal intrahepatic therapy using hAFMSCs has the potential to improve clotting issues in FVIII knockout mice, suggesting it as a potential clinical treatment for individuals with hemophilia A.

Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation.

BACKGROUND: Intrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC. METHODS: Using transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure. RESULTS: DCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes. CONCLUSIONS: Though maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies.

In utero transplantation of myoblasts and adipose-derived mesenchymal stem cells to murine models of Duchenne muscular dystrophy does not lead to engraftment and frequently results in fetal death.

Introduction: Duchenne muscular dystrophy (DMD) is a progressive disease that leads to damage of muscle and myocardium due to genetic abnormalities in the dystrophin gene. In utero cell transplantation that might facilitate allogenic transplantation is worth considering to treat this disease. Methods: We performed allogeneic in utero transplantation of GFP-positive myoblasts and adipose-derived mesenchymal stem cells into murine DMD model animals. The transplantation route in this study was fetal intraperitoneal transplantation and transplacental transplantation. Transplanted animals were examined at 4-weeks old by immunofluorescence staining and RT-qPCR. Results: No GFP-positive cells were found by immunofluorescence staining of skeletal muscle and no GFP mRNA was detected by RT-qPCR in any animal, transplantation method and cell type. Compared with previous reports, myoblast transplantation exhibited an equivalent mortality rate, but adipose-derived stem cell (ASC) transplantation produced a higher mortality rate. Conclusions: In utero transplantation of myoblasts or ASCs to murine models of DMD does not lead to engraftment and, in ASC transplantation primarily, frequently results in fetal death.

Experimental and clinical progress of in utero hematopoietic cell transplantation therapy for congenital disorders.

In utero hematopoietic cell transplantation (IUHCT) is considered a potentially efficient therapeutic approach with relatively few side effects, compared to adult hematopoietic cell transplantation, for various hematological genetic disorders. The principle of IUHCT has been extensively studied in rodent models and in some large animals with close evolutionary similarities to human beings. However, IUHCT has only been used to rebuild human T cell immunity in certain patients with inherent immunodeficiencies. This review will first summarize the animal models utilized for IUHCT investigations and describe the associated outcomes. Recent advances and potential barriers for successful IUHCT are discussed, followed by possible strategies to overcome these barriers experimentally. Lastly, we will outline the progress made towards utilizing IUHCT to treat inherent disorders for patients, list out associated limitations and propose feasible means to promote the efficacy of IUHCT clinically.

Intrauterine Growth Restriction (IUGR) as a potential target for transamniotic stem cell therapy.

BACKGROUND: We sought to determine whether intrauterine growth restriction (IUGR) could be a target for mesenchymal stem cell (MSC)-based transamniotic stem cell therapy (TRASCET). METHODS: Pregnant dams subjected to hypoxia (10.5% O2) cycles had their fetuses divided into four groups: untreated (n = 24) and three groups receiving volume-matched intra-amniotic injections of either saline (sham; n = 16), or suspensions of luciferase-labeled, syngeneic amniotic fluid-derived MSCs that were either native (TRASCET-unprimed; n = 29), or primed by exposure to IFNγ and IL-1ß (TRASCET-primed; n = 31). Normal fetuses served as additional controls (n = 22). Multiple analyses were performed at term. RESULTS: Compared to normal, fetal weights were significantly decreased in all hypoxia groups (p = 0.002 to <0.001), except for TRASCET-primed. Placental efficiency (fetal/placental weight) was significantly decreased in all hypoxia groups (p = 0.002 to <0.001), but normalized in both TRASCET groups. A significant increase in metrial expression of IFNγ in both the untreated and sham groups (p = 0.04 to 0.02) was reversed only in the TRASCET-primed group. Luciferase DNA was present in both TRASCET groups' placentas. CONCLUSIONS: Transamniotic stem cell therapy with primed mesenchymal stem cells reverses some of the effects of intrauterine growth restriction in a rat model. Further study into this novel approach for the treatment of this disease is warranted. LEVEL OF EVIDENCE: N/A (Animal and Laboratory Study).

Routing pathway of syngeneic donor hematopoietic stem cells after simple intra-amniotic delivery.

BACKGROUND: We sought to determine the pathway through which syngeneic hematopoietic stem cells (HSCs) delivered into the amniotic fluid can reach the fetal circulation. METHODS: Lewis rat fetuses were divided in two groups based on the content of intra-amniotic injections performed on gestational day 17 (E17; term=E21-22): either a suspension of luciferase-labeled syngeneic HSCs (n = 137), or acellular luciferase (n = 44). Samples from placenta, chorion, amnion, amniotic fluid, umbilical cord, and 8 fetal sites were procured at 5 daily time points thereafter until term for analysis. RESULTS: When controlled by acellular luciferase, donor HSCs were identified in the amnion, chorion, placenta, and amniotic fluid of fetuses receiving cells at all time points (p = 0.033 to <0.001), peaking first at the amnion and subsequently at the chorion and placenta. Cells could be detected in the fetal liver as early as day 1, progressively expanding to all the other fetal sites over time, in parallel to their increased presence in the chorion and placenta. CONCLUSIONS: The chronology of syngeneic donor hematopoietic stem cell trafficking after intra-amniotic injection is suggestive of controlled routing through the gestational membranes and placenta. Hematogenous donor cell routing is a constituent of transamniotic hematopoietic stem cell therapy, significantly expanding its potential applications.

Fetal hematogenous routing of a donor hematopoietic stem cell line in a healthy syngeneic model of transamniotic stem cell therapy.

BACKGROUND/PURPOSE: In utero administration of hematopoietic stem cells (HSCs) has a variety of actual or potential clinical applications but is hindered by invasive, morbid administration techniques. We sought to determine whether donor HSCs could reach the fetal circulation after simple intra-amniotic delivery in a syngeneic rat model of transamniotic stem cell therapy (TRASCET). METHODS: Pregnant Lewis rat dams underwent volume-matched intra-amniotic injections in all fetuses (n = 90) on gestational day 17 (E17; term=E21-22) of a suspension of commercially available syngeneic Lewis rat HSCs labeled with luciferase (n = 37 fetuses) or an acellular suspension of recombinant luciferase (n = 53). HSC phenotype was confirmed by flow cytometry. Fetuses were euthanized at term for screening of luciferase activity at select anatomical sites. Statistical comparisons were by Fisher's exact test. RESULTS: Among survivors (47/90; 52.2%), donor HSCs were identified selectively in the placenta (p = 0.003), umbilical cord (p < 0.001), bone marrow (p < 0.001), thymus (p = 0.009), bowel (p = 0.003), kidney (p = 0.022), and skin (p < 0.001) when compared with acellular luciferase controls. CONCLUSIONS: Donor hematopoietic stem cells undergo hematogenous routing and can reach the fetal bone marrow after simple intra-amniotic delivery in a syngeneic rat model. Transamniotic stem cell therapy may become a practicable, minimally invasive strategy for the prenatal administration of these cells.

Engraftment potential of maternal adipose-derived stem cells for fetal transplantation.

Advances in prenatal molecular testing have made it possible to diagnose most genetic disorders early in gestation. In utero mesenchymal stem cell (MSC) therapy can be a powerful tool to cure the incurable. With this in mind, this method could ameliorate potential physical and functional damage. However, the presence of maternal T cells trafficking in the fetus during pregnancy is thought to be the major barrier to achieving the engraftment into the fetus. We investigated the possibility of using maternal adipose-derived stem cells (ADSCs) for in utero transplantation to improve engraftment, thus lowering the risk of graft rejection. Herein, fetal brain engraftment using congenic and maternal ADSC grafts was examined via in utero stem cell transplantation in a mouse model. ADSCs were purified using the mesenchymal stem cell markers, PDGFRα, and Sca-1 via fluorescence-activated cell sorting. The PDGFRα+Sca-1+ ADSCs were transplanted into the fetal intracerebroventricular (ICV) at E14.5. The transplanted grafts grew for at least 28 days after in utero transplantation with PDGFRα+Sca-1+ ADSC, and mature neuronal markers were also detected in the grafts. Furthermore, using the maternal sorted ADSCs suppressed the innate immune response, preventing the infiltration of CD8 T cells into the graft. Thus, in utero transplantation into the fetal ICV with the maternal PDGFRα+Sca-1+ ADSCs may be beneficial for the treatment of congenital neurological diseases because of the ability to reduce the responses after in utero stem cell transplantation and differentiate into neuronal lineages.

In utero Therapy for the Treatment of Sickle Cell Disease: Taking Advantage of the Fetal Immune System.

Sickle Cell Disease (SCD) is an autosomal recessive disorder resulting from a ß-globin gene missense mutation and is among the most prevalent severe monogenic disorders worldwide. Haematopoietic stem cell transplantation remains the only curative option for the disease, as most management options focus solely on symptom control. Progress in prenatal diagnosis and fetal therapeutic intervention raises the possibility of in utero treatment. SCD can be diagnosed prenatally in high-risk patients using chorionic villus sampling. Among the possible prenatal treatments, in utero stem cell transplantation (IUSCT) shows the most promise. IUSCT is a non-myeloablative, non-immunosuppressive alternative conferring various unique advantages and may also offer safer postnatal management. Fetal immunologic immaturity could allow engraftment of allogeneic cells before fetal immune system maturation, donor-specific tolerance and lifelong chimerism. In this review, we will discuss SCD, screening and current treatments. We will present the therapeutic rationale for IUSCT, examine the early experimental work and initial human experience, as well as consider primary barriers of clinically implementing IUSCT and the promising approaches to address them.

In Utero Transplantation of Placenta-Derived Mesenchymal Stromal Cells for Potential Fetal Treatment of Hemophilia A.

Hemophilia A (HA) is an X-linked recessive disorder caused by mutations in the factor VIII ( FVIII) gene leading to deficient blood coagulation. The current standard of care is frequent infusions of plasma-derived FVIII or recombinant B-domain-deleted FVIII (BDD-FVIII). While this treatment is effective, many patients eventually develop FVIII inhibitors that limit the effectiveness of the infused FVIII. As a monogenic disorder, HA is an ideal target for gene or cell-based therapy. Several studies have investigated allogeneic stem cell therapy targeting in utero or postnatal treatment of HA but have not been successful in completely correcting HA. Autologous in utero transplantation of mesenchymal stem cells is promising for treatment of HA due to the naive immune status of the fetal environment as well as its potential to prevent transplant rejection and long-term FVIII inhibitor formation. HA can be diagnosed by chorionic villus sampling performed during the first trimester (10 to 13 wk) of gestation. In this study, we used an established protocol and isolated placenta-derived mesenchymal stromal cells (PMSCs) from first trimester chorionic villus tissue and transduced them with lentiviral vector encoding the BDD-FVIII gene. We show that gene-modified PMSCs maintain their immunophenotype and multipotency, express, and secrete high levels of active FVIII. PMSCs were then transplanted at embryonic day 14.5 (E14.5) into wild-type fetuses from time-mated pregnant mice. Four days after birth, pups were checked for engraftment, and varying levels of expression of human green fluorescent protein were found in the organs tested. This study shows feasibility of the approach to obtain PMSCs from first trimester chorionic villus tissue, genetically modify them with the FVIII gene, and transplant them in utero for cell-mediated gene therapy of HA. Future studies will involve evaluation of long-term engraftment, phenotypic correction in HA mice, and prevention of FVIII inhibitor development by this approach.

Maternal and Fetal Immune Response to in Utero Stem Cell Transplantation.

PURPOSE OF REVIEW: In Utero Hematopoietic Cellular Transplantation (IUHCT) is a promising intervention for the non-toxic treatment of congenital disease that hinges on the assumption of fetal immunologic immaturity and an inability to reject a hematopoietic allograft. However, clinical IUCHT has failed except in cases where the fetus is severely immunocompromised. The current review examines recent studies of engraftment barriers stemming from either the fetal or maternal immune system. RECENT FINDINGS: New reports have illuminated roles for maternal humoral and cellular immunity and fetal innate cellular immunity in the resistance to allogeneic IUHCT. These experimental findings have inspired new approaches to overcome these barriers. Despite these advances, postulates regarding a maternal immune barrier to IUHCT provide an inadequate explanation for the well-documented clinical success only in the treatment of fetal immunodeficiency with normal maternal immunity. SUMMARY: Characterization of the maternal and fetal immune response to allogeneic IUHCT provides new insight into the complexity of prenatal tolerance. Future work in this area should aim to provide a unifying explanation for the observed patterns of success and failure with clinical IUHCT.

Fetal stem cell and gene therapy.

Advances in our understanding of stem cells, gene editing, prenatal imaging and fetal interventions have opened up new opportunities for the treatment of congenital diseases either through in-utero stem cell transplantation or in-utero gene therapy. Improvements in ultrasound-guided access to the fetal vasculature have also enhanced the safety and efficacy of cell delivery. The fetal environment offers accessible stem cell niches, localized cell populations with large proliferative potential, and an immune system that is able to acquire donor-specific tolerance. In-utero therapy seeks to take advantage of these factors and has the potential to cure diseases prior to the onset of symptoms, a strategy that offers substantial social and economic benefits. In this article, we examine previous studies in animal models as well as clinical attempts at in-utero therapy. We also discuss the barriers to successful in-utero therapy and future strategies for overcoming these obstacles.

Potential clinical applications of placental stem cells for use in fetal therapy of birth defects.

Placental stem cells are of growing interest for a variety of clinical applications due to their multipotency and ready availability from otherwise frequently discarded biomaterial. Stem cells derived from the placenta have been investigated in a number of disease processes, including wound healing, ischemic heart disease, autoimmune disorders, and chronic lung or liver injury. Fetal intervention for structural congenital defects, such as spina bifida, has rapidly progressed as a field due to advances in maternal-fetal medicine and improving surgical techniques. In utero treatment of structural, as well as non-structural, congenital disorders with cell-based therapies is of particular interest given the immunologic immaturity and immunotolerant environment of the developing fetus. A comprehensive literature review was performed to assess the potential utilization of placenta-derived stem cells for in utero treatment of congenital disorders. Most studies are still in the preclinical phase, utilizing animal models of common congenital disorders. Future research endeavors may include autologous transplantation, gene transfers, induced pluripotent stem cells, or cell-free therapies derived from the stem cell secretome. Though much work still needs to be done, placental stem cells are a promising therapeutic agent for fetal intervention for congenital disease.

Placental stem cells: The promise of curing diseases before birth.

Regenerative medicine is a rapidly expanding and promising field for many diseases and injuries. Stem cells for regenerative therapies have originally been obtained from bone marrow, but are now readily extracted from a variety of adult tissues. Fetal tissue has recently garnered interest for its ease of differentiation into a variety of phenotypes and its relative abundance of pluripotent-linked transcription factors. However, much ethical concern surrounds the methods of obtaining fetal cells. The placenta has emerged as a potential source of fetal derived cells due to its favorable technical and ethical characteristics, as well as its promising therapeutic properties. This preview focuses on providing on overview on the derivation and characteristics of placental derived stem cells as well as delving into their various clinical applications and potential future directions.

Postnatal donor lymphocytes enhance prenatally-created chimerism at the risk of graft-versus-host disease.

The major barrier to clinical application of in utero hematopoietic stem cell transplantation is insufficient chimerism for phenotypic correction of target diseases or induction of graft tolerance. Postnatal donor lymphocyte infusion (DLI) may enhance donor cell levels so as to further facilitate tolerance induction. We created murine mixed chimeras in utero. Chimeras with <10% donor cells were subjected to postnatal DLI to evaluate the effects of DLI on chimerism augmentation and skin tolerance induction. Within one day after DLI, recipients experienced a transient peaking of donor chimerism, which could be as high as 20~40%. However, the transient chimerism peaking didn't benefit donor skin survivals despite immediate skin placement after DLI. In case of fruitful DLI, chimerism augmentation was usually observed after a latent period of 2~4 weeks. Otherwise, chimerism would return to around pre-DLI levels by days 7~14. Peripheral chimerism of >3% could be consistently boosted up to >10%, whereas chimerism of <0.2% hardly showed any significant enhancement. As for chimerism levels of 0.2~3%, chimerism augmentation up to >10% succeeded in 3(15%) of 20 recipients. Notably, chimerism augmentation by postnatal DLI was often associated with unexpected death or graft-versus-host disease (GVHD). In conclusion, transient chimerism augmentation by DLI played no role in facilitating graft tolerance. Substantial augmentation by DLI demanded a threshold chimerism level and posed a serious risk of GVHD to the recipients. It raised the concern about using postnatal DLI to broaden therapeutic horizons of in utero hematopoietic stem cell transplantation.

Target-antigen Detection and Localization of Human Amniotic-derived Cells after in Utero Transplantation in Rats.

Human amniotic-derived cells (hAMCs) have recently raised interest for their differentiation capability and immunomodulatory properties. To assess the feasibility of hAMCs therapeutic treatment during fetal development, we explored the localization of cells derived from the human amniotic membrane in rat organs after in utero transplantation. Rats were sacrificed at different time points and their organs were analyzed for the distribution of hAMCs by immunohistochemistry using an antibody against Human Cytoplasm and through detection of human DNA. Immunohistochemical and PCR analysis showed that most of the rat tissues presented human cells/DNA suggesting a widespread migration of hAMCs after transplantation. We developed an efficient target-antigen detection method based on an immunohistochemical technique that resulted to be highly specific and sensitive to identify the hAMCs into rat tissues.

NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation.

The primary benefits of in utero hematopoietic cellular transplantation (IUHCT) arise from transplanting curative cells prior to the immunologic maturation of the fetus. However, this approach has been routinely successful only in the treatment of congenital immunodeficiency diseases that include an inherent NK cell deficiency despite the existence of normal maternal immunity in either setting. These observations raise the possibility that fetal NK cells function as an early barrier to allogeneic IUHCT. Herein, we summarize the findings of previous studies of prenatal NK cell allospecific tolerance in mice and in humans. Cumulatively, this new information reveals the complexity of the fetal immune response in the setting of rejection or tolerance and illustrates the role for fetal NK cells in the final endorsement of allospecific prenatal tolerance.