Fetal Tolerance: Positive Defence from Within

16 June, 1999

Fetal Tolerance: Positive Defence from Within

During pregnancy a semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens. In a transgenic mouse expressing T-cell receptor specific for a paternal MHC antigen, pregnancy bearing the paternal antigen-positive conceptus reduced the number of the antigen-reactive T-cells. T cell phenotype and responsiveness were restored after delivery (Tafuri A et al, 1995: uid=7570020). Thus, during pregnancy maternal T cells acquire a transient state of tolerance specific for paternal alloantigens. Once upon a time in 1953, Medwar PB considered immunological inertness (tolerance) of the mother, in addition to other possibilities that are by now inconsistent with modern scientific concepts. He already pointed out that survival of allogeneic mammalian conceptus contradicts the principles of tissue transplantation. Since then the notion of immunological "tolerance" has drawn considerable attention.
In several lines of mechanistic evidence for immunological tolerance, Munn DH et al (1998: uid=98378582) has proposed that the fetal allograft actively defends itself from attack by maternal T cells. This positive defence from within is hypothesized based on the observations, namely, 1) certain macrophages induced to express indoleamine 2,3-dioxygenase (IDO) inhibit T cell proliferation in vitro by rapidly consuming tryptophan. IDO is an tryptophan-catablolizing enzyme expressed by trophoblasts and macrophages; 2) Interferon-gamma and other signals from activated T cells induce IDO in macrophages; 3) IDO is also expressed by human syncytiotrophoblast cells at maternal-fetal interface; 4) systemic tryptophan concentration falls during normal pregnancy in a manner correlated with the duration of pregnancy (Schrocksnadel H et al, 1996: uid=96282554).

In addition to pregnancy, IDO-expressing cells are widely distributed in primary and secondary lymphoid organs. Monocytes that have differentiated under the influence of macrophage colony-stimulating factor acquire the ability to suppress T cell proliferation in vitro via rapid and selective degradation of tryptophan by IDO (Munn DH et al, 1999: uid=10224276). IDO was induced in macrophages by a synergistic combination of the T cell-derived signals IFN-gamma and CD40-ligand. Inhibition of IDO with the 1-methyl analogue of tryptophan prevented macrophage-mediated suppression. In the absence of tryptophan, T-cell cell cycle progression halted at a mid-G1 arrest point. Another point of interest is the negative regulation of tryptophan metabolism by transforming growth factor (TGF)-beta. TGF-beta antagonizes many cellular responses to IFN-gamma, and the interaction of these two cytokines plays an important role in maintaining homeostasis during inflammation and repair. In human skin and synovial fibroblasts in vitro, TGF-beta caused time- and dose-dependent abrogation of IFN-gamma-stimulated expression of IDO (Yuan W et al, 1998: uid=9731757). It appears that cellular tryptophan metabolism is under tight immunological control, and that antigen presenting cells (macrophages) in vivo may specifically suppress unwanted T cell responses by IDO expression.

When female mice mated with allogeneic males, IDO transcripts were detected in concepti from 7.5 to 9.5 days post coitus (dpc) but in the placenta only at later gestation times (10.5-13.5 dpc). Treatment (slow release 0.9 mg/hr from polymer pellets) with 1-methyl-tryptophan, an IDO inhibitor, at 4.5 dpc reduced the number of allogeneic concepti at 7.5 to 8.5 dpc and induced extensive hemorrhaging around remaining concepti. The remaining concepti developed normally but at 8.5 to 9.5 dpc showed signs of inflammation and progressive deterioration. No concepti remained at 9.5 dpc (Schrocksnadel H et al, 1996: uid=96282554). In contrast, the inhibitor did not have any effect on syngeneic concepti. Additionally, when female mice with defective RAG-1 (-/-) mated allogeneic males, concepti developed normally even in 1-methyl-tryptophan treatment. RAG-1 gene is required for lymphocyte development. Thus it appears that inhibition of tryptophan catabolism during pregnancy allows maternal lymphocytes to mediate fetal rejection, and that placental cells expressing IDO suppress T cell proliferation and induce maternal tolerance to fetal allografts.

Taken these findings together, it may be conjectured that the placenta (mammalian trophoblast) is not a physical barrier from maternal lymphocytes, and that the fetus, or rather fetal tolerance, is the result of positive immunological defence by fetus itself against attack from maternal T cells.
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