Allogeneic tissues are rejected by the recipient through immune mediated reactions that involves B and T cells. The allogeneic embryonic tissues, however, defy this response. The underlying basis for the lack of rejection of the conceptus by the mother is not clear. In 1953, Medawar hypothesized that the lack of rejection of the embryo by the mother may be due to the following reasons:

1. The separation of the mother from the embryo by a physical barrier.
2. Immuaturity of the embryonic cells to express antigens.
3. Immunologic innertness or tolerance of the mother for the embryonic antigens.

The work of Munn et al, in the August 21, 1998 issue of Science, provides support for the third hypothesis. The authors provide data that shows that mammalian conceptus actively suppresses the maternal T cell activity and therefore, participates in inducing a tolerant state in the mother. This is achieved by the generation of indoleamine 2,3-dioxygenase (IDO) by the trophoblasts. In 1991, Kimumura et al showed that the human syncytiotrophoblasts produce this enzyme. Tthe indoleamine 2,3-dioxygenase activity was not detected in the placenta in the early stages of gestation. IDO was first detected in the placenta at around 14 weeks of gestation. Its amount increased rapidly thereafter and was maintained at high levels till near term. The indoleamine 2,3-dioxygenase activity was significantly lower in placenta with retarded intrauterine development. This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formylkynurenine. Munn et al show that administration of an inhibitor (1-methyl-tryptophan) of the IDO leads to a rapid, T cell induced rejection of all allogeneic embryos. T cells require tryptophan for their proliferation. Exhaustion of the tryptophan leads to the inability of T cells to proliferate. For example, when macrophages produce IDO in response to the interferon gamma, the proliferation of T cells is inhibited. Treatment of the pregnant mice carrying allogeneic embryos led to the loss of the embryos. This loss was associated with degeneration of the embryos, an inflammatory response and surrounding areas of hemorrhage. In contrast, the syngeneic embryos were not affected by this treatment. Munn et al also examined the role of T cells in this event. RAG ^-/- female mice were mated with B6 males. The RAG ^-/- phenotype leads to lack of lymphocyte development. Treatment of the pregnant RAG ^-/- female mice with the 1-methyl-tryptophan had no impact on the survival of the embryos and these animals carried their embryos to term. However, when the RAG ^-/- mice were reconstituted with H-2K^b specific T cells, the treatment led to fetal loss. These results support the notion that IDO-expressing cells of the fetus lead to the tolerance of the maternal T cells. This tolerance may be achieved by the local inhibition of T cell proliferation at the embryo-maternal interface. The data also provide support for existence of fetal antigen driven maternal T responses which are inconsistent with the first and second hypothesis of Medawar. These findings have great implications. For example, it is possible that defects in the production of the IDO may account for the habitual abortion in women or immune responses seen in a variety of autoimmune diseases. Validation of such scenarios, could open the possibility to treat such conditions in humans.

REFERENCES:

Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998 Aug 21;281(5380):1191-1193

Medawar, P. B. : Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7: 320-338, 1953.

Kamimura S, Eguchi K, Yonezawa M, Sekiba K: Localization and developmental change of indoleamine 2,3-dioxygenase activity in the human placenta.Acta Med Okayama 1991 Jun;45(3):135-139

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