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

Abstract

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.

Tolerogenic Splenic IDO+Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis

“…IDO, which degrades the essential amino acid tryptophan, is important in host defenses and immunosuppression for the maintenance of tolerance in cancer, transplantation [29], and EAE [30]. This enzyme also influences the crosstalk between Tregs and DCs [10].…”

CD71+ Erythroid Suppressor Cells Promote Fetomaternal Tolerance through Arginase-2 and PDL-1

“…There are multiple mechanisms that have evolved during gestation to block the immunological rejection of the fetus. For instance, IDO, which deprives cells from tryptophan, is crucial to prevent accumulation and proliferation of T cells in the fetomaternal interface (4,5). Furthermore, interactions of FAS ligand expressed in uterus and placenta with FAS molecule on activated T cells may cause apoptosis of these cells in fetomaternal interface (6).…”

Placenta-Derived Mesenchymal Stromal Cells: Modulation of Immunity and Inflammation

“…IDO is a hemecontaining enzyme that catabolizes the essential amino acid tryptophan into L-kynurenine. IDO-induced tryptophan degradation results in T cell cycle arrest in the G1 phase and serves as an instrumental mechanism for maintaining immune cell homeostasis and peripheral tolerance [8]. IDO gene expression and activity were induced in co-cultures of pMSC with MLRs/ BTRs [6,7,9] and replenishment of tryptophan or treatment with IDO blocking compounds were shown to impair the antiproliferative abilities of pMSC [9,10].…”