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

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.

Fetal-Specific CD8+ Cytotoxic T Cell Responses Develop during Normal Human Pregnancy and Exhibit Broad Functional Capacity

“…In "villitis of unknown etiology," excessive infiltration of maternal CD8 + T cells into the villous tree of the placenta is associated with fetal growth restriction, pregnancy loss, and stillbirth (55). Furthermore, the potential impact on fetal physiology was recently illustrated by the demonstration that maternal T cells trafficking into the fetal circulation are the main barrier to engraftment following in utero hematopoietic cell transplantation (56). Our observations indicate that the study of adaptive T cell immune responses against fetal tissue should be an important area for future obstetric investigation.…”

Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice

“…3 In mice, there is excellent engraftment of fully allogeneic HSCs in fetal recipients, 4,5 with donor-specific tolerance in chimeras. [6][7][8] In fact, it has been shown that the fetal immune response is not a barrier to engraftment as long as the maternal immune response is controlled. 7,8 Ideally, the introduction of a new antigen in the fetal environment should recapitulate multiple mechanisms of self-tolerance and lead to durable engraftment.…”

“…[6][7][8] In fact, it has been shown that the fetal immune response is not a barrier to engraftment as long as the maternal immune response is controlled. 7,8 Ideally, the introduction of a new antigen in the fetal environment should recapitulate multiple mechanisms of self-tolerance and lead to durable engraftment. The mechanisms by which HSC transplantation leads to donor-specific tolerance have been studied extensively in the setting of postnatal BMT.…”

Isolation and Characteristics of Mesenchymal Stromal Cells from Different Parts of Placenta

“…It should fetal circulation than in maternal that probably promote cell trafficking through placenta [15]. Nijagal et al shown that inflammatory disease (autoimmune processes, complication during pregnancy, congenital anomalies and others) [16] during pregnancy changes cell trafficking [17]. Similar to maternal cells, fetal cells were detected into different maternal organs and tissues: liver, kidney, bone marrow [18].…”