Mar 24, 2011 - aim of transplanting donor stem cells to replace or repair defective cells of the ... with T-cell deficiency than in fetuses of wild- type mothers or of ...
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In Utero Hematopoietic Stem-Cell Transplantation — A Match for Mom Ornella Parolini, Ph.D. Once researchers recognized that adult stem cells can generate multiple cell types and contribute to tissue homeostasis, it became conceivable to exploit this potential to treat genetic or acquired disorders characterized by tissue degeneration or organ dysfunction. The concept of regenerative medicine was thus born, with the general aim of transplanting donor stem cells to replace or repair defective cells of the host. Unfortunately, in the case of an HLA mismatch between donor and recipient, transplantation is hampered by the risks of immunologic recognition and rejection of the graft. However, a recent article by Nijagal and colleagues1 revives the discussion of the potential advantages of transplanting stem cells into the fetus early in gestation. Because in utero stem-cell transplantation can be carried out when the immune system is immature, it provides the theoretical opportunity to induce fetal tolerance of the foreign cells and thereby avoid rejection and the need for immunosuppressive therapy. For these reasons, this potential clinical approach is attractive for any disorder that is amenable to stemcell transplantation and that can be prenatally diagnosed. However, despite successful results of in utero transplantation in animal models, achieved for the most part with hematopoietic stem cells (HSCs), positive outcomes of this procedure in humans have been limited to cases of inherited immunodeficiency diseases.2-4 One of the main hurdles to widespread application and success of in utero stem-cell transplantation is the difficulty in achieving adequate levels of engraftment. Nijagal and colleagues tested their hypothesis that maternal cells trafficking into the fetus impede effective in utero stem-cell transplantation by mounting a sort of “immune protection” of the fetus, in which maternal cells effect the
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rejection of cells allogeneic to both mother and fetus. Using mouse models, these researchers tested their hypothesis in a series of experiments to evaluate the role of the maternal immune response in limiting engraftment. First they found that in utero transplantation of fetal HSCs elicited an increase in trafficking of maternal T cells to the fetal blood. To test the hypothesis that maternal cells play a pivotal role in the fetal engraftment of allogeneic cells, they transferred allogeneic fetal HSCs into fetuses of mothers with experimentally induced B-cell or T-cell deficiency (Fig. 1). Levels of engraftment were significantly higher in fetuses of mothers with T-cell deficiency than in fetuses of wildtype mothers or of mothers with B-cell deficiency. Finally, when in utero stem-cell transplantation was performed with HSCs matched to the mother, similar levels of engraftment were observed in fetal recipients of syngeneic and allogeneic fetal grafts. The evidence put forward is clear and striking, although further research is warranted to confirm these findings, as well as to determine whether maternal T cells are critical for the success of in utero stem-cell transplantation in other animal models. Differences in placentation between animal species might predict differences in maternal-cell trafficking and thus the extent to which the observed phenomenon in mice is relevant to other animals. However, considering that the same types of hemochorial placentation and fetal–maternal chimerism have been described in humans, the conclusion of Nijagal et al. may be relevant to humans. The clinical relevance of this study lies in the potential for improving engraftment with the use of cells that are either harvested from or matched to the mother’s cells (Fig. 1). Although collecting stem cells from pregnant women presents
n engl j med 364;12 nejm.org march 24, 2011
clinical implicatons of basic research
A
Figure 1. Intrauterine Transplantation and Maternal T Cells. A recent study by Nijagal and colleagues1 highlights a key role of maternal T cells in limiting engraftment after in utero transplantation, in which allogeneic fetal hematopoietic stem cells (HSCs) were transplanted into the fetuses of wild-type mice (Panel A) and of mice lacking B cells (Panel B) or T cells (Panel C). Only T-cell deficiency resulted in significant improvement in engraftment levels, as compared with the levels in wildtype mothers. A notable level of engraftment was also observed after transplantation of fetal HSCs that were genetically matched to the mother (Panel D). Taken together, these results suggest that maternal T cells are responsible for failure of engraftment. It is therefore possible that the clinical success of in utero stem-cell transplantation could be improved by transplanting cells harvested from or matched to the mother’s cells (Panel E).
Allogeneic fetal hematopoietic stem cells Wild-type mother
B
Allogeneic fetal hematopoietic stem cells Mother lacking B cells
C
Allogeneic fetal hematopoietic stem cells Mother lacking T cells
D
Significant improvement in engraftment levels
Matched maternal cells Wild-type mother
Significant improvement in engraftment levels
some obstacles, they are not insurmountable, and such an approach may confer advantages that would extend the clinical applicability of in utero stem-cell transplantation beyond transplantation of HSCs to include other cell types — such as mesenchymal stromal cells — for the treatment of congenital diseases outside the hematopoietic system. Finally, the notion that maternal T cells are responsible for the rejection of allogeneic transplanted HSCs and are therefore critical to the success of engraftment underscores the complex and paradoxical relationship between mother and fetus during pregnancy. Disclosure forms provided by the author are available with the full text of this article at NEJM.org From Centro di Ricerca E. Menni, Fondazione PoliambulanzaIstituto Ospedaliero, Brescia, Italy.
E Maternal cells
Matched maternal cells
1. Nijagal A, Wegorzewska M, Jarvis E, Le T, Tang Q, Macken-
zie TC. Maternal T COLOR cells limit FIGURE engraftment after in utero hematopoietic cell transplantation in mice. J Clin Invest 2011;121:582Rev4 02/24/11 92. 2. Wengler A, Frusca T, et al. In-utero transAuthor GS, Lanfranchi Dr. Parolini plantation Fig # of parental 1 CD34 haematopoietic progenitor cells in a patient with X-linked severe combined immunodeficiency Title (SCIDXI). Lancet 1996;348:1484-7. ME AW, Roncarolo MG, Puck JM, et al. Treatment of X3. Flake linkedDEsevere combined immunodeficiency by in utero transPhimister plantation bone Muller marrow. N Engl J Med 1996;335:1806Daniel Artist of paternal 10. AUTHOR PLEASE NOTE: 4. Peranteau Endo M, Flake AW. Evidence for Figure hasWH, been redrawn and Adibe type hasOO, been reset Please check an immune barrier after incarefully utero hematopoietic-cell transplantation. Blood Issue date2007;109:1331-3.
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Copyright © 2011 Massachusetts Medical Society.
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