Article

Maternal T cells limit engraftment after In utero hematopoietic cell transplantation in mice

Eli and Edythe Broad Center of Regeneration Medicine, San Francisco, California, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 02/2011; 121(2):582-92. DOI: 10.1172/JCI44907
Source: PubMed

ABSTRACT

Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

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Available from: Marta Wegorzewska
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    • "At the same time, a lack of maternal immunization to donor alloantigen has been shown to be indispensable for a long-term engraftment (reviewed in ref. (Nijagal et al. 2012; Pearson and Flake 2013)). In this respect, maternal donor cells are beneficial to IUHCT (Nijagal et al. 2011; Parolini 2011) because they do not induce immunoreactions in the uterus, and maternal antibodies would not exclude engrafted donor cells in the fetuses. The B6.C-H2 bm1 /ByBir-Gus mps mouse strain is an original MPSVII murine model of Sly disease (human MPSVII) (Sly et al. 1973), and lacks β-glucuronidase (GUSB) (Birkenmeier et al. 1989). "
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    ABSTRACT: Background In utero hematopoietic cell transplantation (IUHCT) has been performed in Mucopolysaccharidosis Type VII (MPSVII) mice, but a lifelong engraftment of allogeneic donor cells has not been achieved. In this study, we sought to confirm a lifelong engraftment of allogeneic donor cells immunologically matched to the mother and to achieve partial rescue of phenotypes in the original MPSVII strain through IUHCT by intravenous injection.Methods We performed in vitro fertilization in a MPSVII murine model and transferred affected embryos to ICR/B6-GFP surrogate mothers in cases where fetuses receiving IUHCT were all homozygous. Lineage-depleted cells from ICR/B6-GFP mice were injected intravenously at E14.5. Chimerism was confirmed by flow cytometry at 4 weeks after birth, and β-glucuronidase activity in serum and several phenotypes were assessed at 8 weeks of age or later.ResultsDonor cells in chimeric mice from ICR/B6-GFP mothers were detected at death, and were confirmed in the bone marrow, thymus, spleens, livers, and several tissues including the brains of sacrificed chimeric mice. Although the serum enzyme activity of chimeric mice was extremely low, the engraftment rate of donor cells correlated with enzyme activity. Furthermore, improvement of bone structure and rescue of reproductive ability were confirmed in our limited preclinical study.Conclusions We confirmed the lifelong engraftment of donor cells in an original immunocompetent MPSVII murine model using intravenous IUHCT with cells immunologically matched to the mother without myeloablation, and the improvement of several phenotypes.
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    • "Regenerative therapies are particularly promising for use in prenatal repair because of the inherent plasticity and immunotolerance unique to the developing fetal environment . The fetus has long been recognized to have a remarkable ability to heal after injury [20], and work with in utero hematopoietic stem cell transplantation has shown that the fetal environment offers considerable advantages for the success of stem cell transplantation [21]. The immunologic immaturity of the early gestational fetus provides a unique opportunity for induction of donorspecific tolerance to allogenic cells [22]. "
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    ABSTRACT: Spinal cord damage in myelomeningocele (MMC) results from abnormal cord development and subsequent local trauma. Prenatal surgery prevents additional neural injury. However, existing damage is not reversed. Biodegradable nanofibrous scaffolds (NSs) promote regeneration of neural tissues. They mimic the microtopography of the extracellular matrix and guide tissue formation and organization. The purpose of this pilot study was to evaluate the practicality and safety of using biodegradable NS as a regenerative device in prenatal MMC repair. Two fetal lambs underwent a surgically induced MMC defect followed by open fetal repair using aligned biodegradable NS. Lambs were killed at day 138. Spinal cords were examined for inflammation or fibrosis and stained for spinal cord architecture, myelin, and neuron cell bodies. Prenatal repair with NS demonstrated technical feasibility. There was no evidence of a surrounding inflammatory response or foreign-body reaction to the scaffold. Biodegradable NS can be used surgically for the prenatal repair of MMC in a large animal model and does not appear to elicit an inflammatory or fibrotic reaction in fetal tissue. Further studies will determine their potential for neural cell infiltration, delivery of growth factors, drugs or stem cells, and functional recovery greater than standard repair.
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    • "In nonimmunodeficient fetuses, tolerance was also apparently induced but, in contrast with SCID patients, the number of donor cells did not expand significantly over the years. Various hypotheses may account for this limited development of donor cells: selective advantage of host stem cells over donor stem cells, lack of “space” in the hematopoietic niches, allogeneic reactions from the progressively immunomature lymphocytes of the host, and allogeneic reactions from the maternal T-cells that have been shown to reduce engraftment after in utero SCT [20]. When allogeneic and autologous SCT in fetal sheep were compared, however, no significant difference was found between the two groups [21]. "
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    ABSTRACT: Patients transplanted with HLA-mismatched stem cells from fetal livers develop transplantation tolerance to donor antigens. Engraftment needs no conditioning regimen prior to transplantation in neonates with severe combined immunodeficiency disease or in human fetal patients having not yet developed any immune maturity, especially T-cell differentiation. The chimeric patients have donor-derived T lymphocytes which progressively demonstrate positive interactions with other host cells. They also can be shown to be tolerant toward both host and donor antigens. The latter tolerance relies upon clonal deletion from the T-cell repertoire, and it results from the contact between thymocytes of donor origin and dendritic cells or macrophages also deriving from donor stem cells. The former tolerance does not imply clonal deletion of T-cells with host reactivity. Numerous T-cells recognizing the allogeneic, host-type antigens are identified in these patients, but these cells are anergized, following interaction with epithelial cells of the host thymus. Induction of transplantation tolerance at the fetal stage requires minimal engraftment only; in the future it will be possible to further amplify the clinical benefit, using additional cell transplants after birth.
    Full-text · Article · Aug 2011 · Journal of Transplantation
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