The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology

Abstract

The regulation of the interaction between the immune system and antigens, which may lead to the induction of immune tolerance, is critical both under physiologic conditions and in different pathological settings. In the past few years, major strides have been made in our understanding of the molecular and cellular bases of this process. Novel IntroductionIndoleamine 2,3-dioxygenase (IDO) is an intracellular hemecontaining enzyme that catalyzes the initial rate-limiting step in tryptophan degradation along the kynurenine pathway. 1 Tryptophan starvation by IDO consumption inhibits T-cell activation, 1-3 whereas products of tryptophan catabolism, such as kynurenine derivatives and O 2 free radicals, regulate T-cell proliferation and survival. 1,4 IDO is widely expressed in human tissues and cell subsets and is induced during inflammation by IFN-␥ and other inflammatory cytokines. 5 Recent works have demonstrated a crucial role for IDO in the induction of immune tolerance during infection, pregnancy, transplantation, autoimmunity, and neoplasias, including hematologic malignancies. 1,6,7 In the hematology field, regulatory dendritic cells (DCs) and bone marrow (BM)-derived mesenchymal stem cells (MSCs) expressing IDO have the capacity to suppress T-cell responses to autoantigens and alloantigens. 8,9 Moreover, acute myeloid leukemia (AML) cells have been recently demonstrated to express a functionally active form of the IDO protein, which is capable of inhibiting the T-cell response through the expansion of regulatory T cells (T regs ). 10 Although several reviews addressing the enzymatic activity of IDO have recently been published, the aim of the present paper is to summarize the most recent data about IDO expression in hematopoietic cells and its role as a potential therapeutic target in hematologic malignancies. General and biologic aspectsTryptophan is an amino acid required by all life forms for protein synthesis and other important metabolic functions, such as the synthesis of the essential cellular factor, nicotinamide adenine dinucleotide (NADϩ) and the synthesis of serotonin. Dietary tryptophan is delivered to the liver through the hepatic portal system, and the pool of tryptophan that is not used for protein synthesis can either be degraded in the liver or distributed into the bloodstream where it is captured and used by cells throughout the body. Since the 1970s, several studies have demonstrated that 2 different enzymes initiate the catabolism of tryptophan through a series of metabolic steps known collectively as the kynurenine pathway. Tryptophan 2,3-dioxygenase, or TDO, is an enzyme that is primarily expressed in the liver, is induced by tryptophan and metabolic steroids, and is highly specific for tryptophan. In contrast, IDO is found in many tissues, is induced by inflammatory stimuli, and has less substrate specificity. More recently, a novel gene with homology to IDO has been reported and then subsequently demonstrated to encode an enzyme that catabolizes tryptophan. 11,12 This enzyme has bee...

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“…This effect could be exerted either through cell-tocell contact or by the release of soluble factors. 6,7 Moreover, the conditioning regimen and/or the occurrence of GvHD may sustain an inflammatory response in the BM which may further interfere with the normal hematopoiesis. 8 Notably, inflammation has been associated with promotion and progression of solid tumors, and may correlate with a poor prognosis.…”

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“…IDO, which is inducible by various inflammatory stimuli, is widely distributed in various immune and nonimmune cell types, and downregulates adaptive immune response and inflammation as well. [7][8][9][10] Recently, we have shown that IDO plays a significant role in the impaired adaptive immunity that characterizes HD patients. 11 Considering that inflammation contributes to atherosclerosis progression in HD patients, 12 evaluation of a possible role of this immunomodulatory enzyme is interesting.…”

“…Serum interleukin-6 (IL-6) and C-reactive protein (CRP) were also measured because inflammation usually accompanies HD, [20][21][22] has been incriminated for atherosclerosis progression in this population, 12 and upregulates IDO. 7,8 …”