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: 13.77). 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, Aug 21, 2015
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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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