Implication of indolamine 2,3 dioxygenase in the tolerance toward fetuses, tumors, and allografts

Mammalian IDO is a heme-containing enzyme whose main activity in mammals is to degrade the essential amino acid tryp into L-kynurenine. Although the link between its enzymatic activity and the immune response is not straightforward, several lines of evidence suggest that this enzyme is involved in fighting infections and paradoxically, also in the establishment of the immune tolerance associated with fetus implantation and with the development of oncogenic processes. IDO is associated with the successful development of the fetus. It participates early in pregnancy to the efficient invasion of the uterine mucosa by the nascent trophoblast and remains active throughout the whole process, as illustrated by the decrease in systemic tryp from the second trimester of gestation and the return to normal values after delivery. The short-term activation of IDO in response to invading pathogens and emerging tumors participates in the elimination of these threats, whereas the sustained activation of IDO often results in a state of immune tolerance that may favor chronic infections and the uncontrolled proliferation of malignant cells. However, despite these potential deleterious effects of IDO, the enzyme is instrumental in maintaining the peripheral tolerance that is required to avoid autoimmune diseases. Below, we review the implication of IDO activation upon the physiological development of the fetus and the pathological development of tumors and discuss whether such an enzyme could be used as a therapeutic tool to decrease the rate of allograft rejections via its potent immunomodulatory properties.