Allergic disorders

Allergic disorders are among health issues that create a major economic problem due to the complications of the innate and adaptive immune system [1]. During the last few decades, the prevalence of allergies has dramatically increased. Today, allergies are among the prevalent chronic disorders in most countries [2, 3]. On the other hand, immune regulation is a highly advanced biological response that can create natural immunity and inflammation as well as the adaptive immunity of controlled and self-tolerance development [4, 5].

IDO structure and characterization

Tryptophan (TRP) is a crucial amino acid and a substrate for numerous proteins used by various cells in the human body [6]. This amino acid exists in low quantities in the body, and it generally flows in the blood and plasma, attached to albumin [7]. Insufficient nutritional consumption of TRP can result in an undesirable nitrogen equilibrium and a decline of muscle mass, weight, and brain mass [8]. The mean serum level of TRP in human blood must be 73 ± 14.9 μmol/l [9].

TRP is significant for cell survival and protein production. Moreover, it is an antecedent for serotonin and other beneficial molecules in the brain tissue, including melatonin and niacin, and it guides immune responses in mammals [10, 11]. Furthermore, it is a valuable backup for the Kynurenine pathway (KYN) [12, 13]. TRP is processed via three diverse biosynthetic paths, i.e., (a) the creation of KYN byproducts, (b) the production of serotonin [14], and (c) the biosynthesis of proteins (Fig. 1). The main supervisor enzyme in this path, which is common in several tissues [13], is indoleamine-2,3-dioxygenase (IDO). Current studies show that KYN metabolites have immunosuppressive and antimicrobial characteristics [15, 16]. By catabolizing TRP, cells secreting the IDO enzyme can facilitate strong local properties on natural and specific immune responses to inflammatory stimuli [11]. IDO is composed of 407 amino acids, and it is an intracellular monomeric [6] that is responsible for the primary phase in the catabolism of TRP into N-formyl-Kynurenine [17].

Fig. 1
figure 1

A Normal tryptophan metabolism: Tryptophan degradation through three pathways that result in protein synthesis, melatonin production, and the main product kynurenine. B Th1 immune response activation: IFN-γ is the main significant stimulator of IDO1. The decomposition of tryptophan in the kynurenine path results in the addition of products, some of which are created to stimulate Tregs to reduce T cell motivation. Decreasing tryptophan due to degradation by IDO1 restricts protein biosynthesis and melatonin production. (T reg = regulatory T cell; 3HO kynurenine = 3-hyroxykynurenine)

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The two types of the IDO enzyme are IDO1 and IDO2, both of which change TRP to KYN with different levels of activity [18]. IDO2 is less frequently expressed than IDO1, and it only has 3–5% of the enzymatic activity of IDO1 [18, 19]. The IDO enzyme is determined by the IDO1 gene, which is situated on chromosome 8 [20]. IDO1 is expressed in a wide variety of mammalian cells related to immune purpose, as well as specialized immune cells (antigen-presenting cells (APC)), or cells that consult immune concession to tissues. However, the expression of IDO1 is not permanent, and it relates to the immunologic signals mainly engaged via interferons)type I and II( (IFNs) [21]. Moreover, IDO is significantly prompted in dendritic cells (CD123+ CCR6+ CD11b− CD86+ plasmacytoid dendritic cells), which limits infection and avoids overexpressed host responses [17, 22]. IDO also appears to facilitate the switch from natural to specific immunity [23]. In non-inflammatory conditions, IDO appears to facilitate tolerance to self [24].

Here, we discuss the current evolution in understanding immunomodulatory and immunoregulatory characteristics of IDO in allergic responses. The presented developments pinpoint potential new goals for therapy in allergic disorders.

IDO and immune responses

The common task of the immune system is to discriminate among familiar and unfamiliar and to recruit defensive immune responses in the existence of a hurtful, unfamiliar antigen. This equilibrium between the beginning and destruction of the immune response depends on an extraordinary amount of controller mechanisms [25]. Currently, the impact of TRP catabolism via the KYN path has been presented in one of the immune tolerance mechanisms. The enzymes that break TRP through this pathway are established in various cells, including the cells of the immune system [6]. IDO expression can be stimulated in the lungs, the brain, the gut, multiple malignancies, kidneys, plasmacytoid dendritic cells (pDCs) inside the spleen, and the draining lymph nodes [26, 27]. In standard physiologic character, IDO is significant in controlling immune motivation to antigenic encounters at mucosal surfaces in the lungs and the digestive tract [28, 29]. Numerous co-stimulators are mandatory for the activation and appearance of IDO-1/IDO-2. They contain cytokines (Tumor necrosis factor-alpha (TNF-α), Transforming growth factor-beta (TGF-β), and interferon (IFN)), lipopolysaccharides similar to amyloid peptides, several human immunodeficiency virus (HIV) antigens, and numerous ligands of Toll-like receptor) TLR [14, 30, 31]. Principally, IFN‐γ strongly stimulates the catalytic activity of IDO, reducing TRP and increasing immunoregulatory KYN, which will possibly raise regulatory T-cell (Treg) extension. Prompted Treg cells consume TGF‐β to preserve an IDO-related regulatory milieu, with the IDO frequently working as an indicating molecule [24]. IFN-γ via co-stimulation molecules stimulated DCs to present practical IDO, decrease TRP, and increase the growth of KYN products and consequent Th-cell reticence. Common results show the special stimulation of apoptosis in Th1 cells owing to the improved vulnerability of Th1 cells to KYN metabolites [32, 33]. Furthermore, with regard to the impacts of TRP on Th(1, 2, and 17) cells, current data show that TRP catabolites influence natural lymphocytes [34].

IDO is a useful regulator of the active equilibrium among immunity and tolerance, and it is essential for adaptive immunity, immune investigation instruments, and antiviral protection, and in confronting intracellular pathogens [35, 36]. IDO1 prevents the propagation of T cells via the reduction of TRP and/or via manufacturing bioactive catabolites. Therefore, TRP metabolism was revealed to be strongly involved in immunomodulation [37]. A character of stimulated IDO1 was shown through the rise in the KYN/TRP ratio since KYN/TRP is associated with the density of the immune stimulation, such as autoimmune, infections, and neurodegenerative conditions [38, 39]. Through degrading TRP, IDO1 modifies native and total TRP density and initiates the production of immunoregulatory and neuroactive TRP products. Munn et al. used a mouse model to show that IDO1 stimulation indicates a significant feature in the formation of immune tolerance against the embryo, and they have proven the placenta as an immune-privileged place to avoid denial of the embryo. The known controlling activities of the IDO pathway mainly act on T, Natural killer (NK) cell, macrophages, and dendritic cell (DCs) cells. IDO causes naive T cells to discriminate into T regulatory cells (Treg cells, CD4+CD25+FoxP3+) that spread general anergy to the presented antigens (Fig. 1) [40]. These catabolites do not have a similar result on Th2 cells, so improved IDO movement seems to tilt Th- cell divergence to a Th2 phenotype [41]. Moreover, IDO encourages Treg differentiation, the initiation of apoptosis in numerous subgroups, and T cell receptor (TCR) stimulation. IDO’s activities on NK cells cause the downregulation of motivating receptors and cell death. Moreover, IDO has been revealed to regulate DCs development and migration [42]. DCs expressing IDO suppress T-cell propagation, distinction, effector functions, and sustainability, either through direct effects on T cells or via affecting IDO on the DCs [37]. In other words, IDO is a general regulator of inflammation [43]. Also, studies suggest the contrasting roles that IDO1 and IDO2 play in immune responses, with IDO1 facilitating T cell suppressive effects and IDO2 working traditionally in B cells as a proinflammatory mediator of B cell responses [44].

Immunomodulatory and immunoregulatory roles of IDO

Set-out immune system by critical amino acid famishment via IDO happens through two separate methods. The first is imitating a natural defensive response against inflammatory harm. Secondly, there is an interaction linking Treg cells and APCs, which results in additional upregulation of IDO, capable of limiting T-cell propagation and endorsing Treg cell extension by infectious tolerance [45,46,47]. The first detection of immunomodulatory properties of IDO enzyme was prepared in 1984 once IFN-γ stimulated TRP deterioration and obstructed the growth of Toxoplasma gondii in human fibroblasts. This revealed the IFN-γ stimulation of IDO and the initiation of the KYN path, TRP interruption, and gathering of KYN products [48]. This first immunoregulatory role of TRP suggested the role of IDO products in the limited cellular reduction of TRP that plays two main roles: firstly, TRP famishment of microbes, triggering demise, and, secondly, helping Th2 cell polarity. Commonly, a Th2 polarity facilitates both the initiation and preservation of immunity by antibodies. This is different from a Th1 shifting that facilitates cellular immunity and plays a significant role in inflammation and autoimmunity. Previous works have referred to a regulatory subgroup of macrophages and DCs presenting IDO that have the capability to stimulate cell cycle halt in T cells, depending on IDO breakdown [49, 50]. More recent evidence shows that TRP famishment by IDO is not achieved solely by disabling TCR; rather, it occurs together with the stimulation of FAS-correlated cell phase halt in the mid G1 stage of T-cell death, clonal energy, and the prevention of specific cellular responses [50, 51]. The current consensus is that the stimulation of the IDO-KYN path causes T-cell apoptosis [52], T-cell anergy [52], Th17 and Tregs cells propagation [53], and the aberration of the Th1/Th2 response [53]. The downstream products of TRP overwhelm immune reactivity via directly interacting with many types of immune cells, especially effector T lymphocytes [54, 55]. The signaling activity of IDO in DCs has been shown, and these DCs are steadily switched into regulatory DCs [4]. The IFN–IDO pivot is also capable of negative regulation of immune responses to reduce damage to immune-dependent tissues and organs in the precise setting of infectious immunity [56], over-reactive inflammatory responses [57], and autoimmunity [58]. This inherited counter-regulatory mechanism has three parts [59]. First, the products of TRP catabolism have developed direct immunoregulatory roles [60]. Second, the collective impacts of TRP famishment and Kynurenines [33] have shown a potential for motivating T-cell distinction to a Treg phenotype [61]. As a final point, the IDO method has developed essential tools for protective resident homeostasis in the intermediary response from natural to adaptive immunity [62, 63]. Thus, the probable immunoregulatory role of IDO in resisting attacking microbes, counter-regulating extreme immune activation in autoimmunity, decontrolling host immune response via cancer cells expressing it, and prompting graft tolerance in transplantation, and in maternal–fetal tolerance are now well documented.

IDO role in diseases

Once pathogens attack host cells, they stimulate the natural immunity and provoke the production of chemokines and cytokines, i.e., worker cells of the immune system that facilitate pathogen sanction. In particular, IFNs are significant mediators of natural immunity that prevent the harmful impacts of several viruses [64]. Presently, evaluations on the characteristics of IDO in cancer [65], HIV [66], antitumor immunity [67], therapeutic potentials [13], the stimulation of the IDO motion and signaling [4], allogeneic engraftment of skin substitutes [68], and posttranslational modifications [69] have been performed. The pharmacologic dampening of IDO causes noticeable aggravation of inflammation and exacerbates the signs of disorder in a murine model of inflammatory bowel disease [70]. Several pre-clinical and clinical studies are focusing on a number of new mixtures with chemotherapeutics and IDO1, IDO2, or both enzyme inhibitors in cancer therapy. In a tumor, IDO appears to reduce the employment of antitumor immune cells, prompt tolerance to tumor Ags, and thus simplify immune escape [71, 72]. IDO helps generate a tolerogenic situation in the tumor and the tumor-draining lymph nodes, both via the direct destruction of T cells and the improvement of limited Treg-mediated immunosuppression [71] (Fig. 1).

Role of IDO in allergic diseases

A point requiring specific attention is the role of TRP metabolism in allergic disorders. An immune aberration to the Th2-type immune pattern is involved in the pathogenesis of allergic diseases. Inflammation due to allergic reactions is considered by the upregulation of cytokines correlated to Th2 [73]. The latter is a robust stimulator of the IDO enzyme, which destroys the critical amino acid TRP as part of an anti-proliferative approach of immunocompetent cells to stop the development of infected and tumorous cells [74].

The immunosuppressive role of IDO in response to an allergen was first understood in a study by Bubnoff Von et al. [75]. They showed the KYN/TRP ratio to be decreased, together with lesser TRP and greater KYN amounts, in adults susceptive to aeroallergens who were asymptomatic compared to those who displayed signs. Buyuktiryaki et al. described lesser serum KYN/TRP ratios in children with a food allergy that persevered as opposed to healthy children or in food allergic children who had established tolerance [76]. Furthermore, recent data show that the stimulation of the KYN-IDO path and the subsequent reduction of serum TRP and the growth of TRP products regulate the allergic situation [52]. The mechanism of the IDO-stimulated tolerance motivation can potentially vary; however, the stimulation of Treg cells may be the main feature of the control role over inflammation due to allergic stimuli [21]. Additionally, the microbial motivation of the IDO pathway by TLR might also help determine the result of allergic inflammation [53, 77]. IDO has also been identified in eosinophils, lung epithelial cells, and endothelial cells, which indicates a role in allergic reactions [78]. The role of IDO in eosinophils (ESOs) is also inhibitory or stimulatory on Th1 and Th2 cells related to the previous sensitization and inflammatory pattern [79, 80]. IDO stimulation in ESOs might mediate in-vitro and in-vivo polarization of Th2 [81]. The quantity and perseverance of IDO-presenting ESOs in lymphoid tissues may emphasize the apoptotic result on Th1, formerly believed to be related only with IDO-presenting tolerogenic DCs, and, therefore, preserve Th2 preference [81] (Fig. 2). It was recently described that the experimentally stimulated intensification of rhinovirus asthma was associated with systemic TRP and quinolinic acid amounts. Moreover, it was established that pulmonary IDO1 actions were lower and serum tryptophan amounts were higher in patients with allergic asthma [82]. In addition, TNF-α in allergic diseases, in combination with IFN-γ, can stimulate IDO1 action [83].

Fig. 2
figure 2

The production of cytokines, such as TNF-α, in the process of allergic diseases causes the production of IDO enzymes. IDO enzymes play a role in the production of regulatory T cells by metabolizing tryptophan to kanamycin and its metabolites, which negatively regulate Th2 cells and reduce the allergic symptom (T reg = regulatory T cell; 3HO kynurenine = 3-hyroxykynurenine)

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The ligation of the FcεRI through allergens on monocytes cells isolated from atopic people stimulates the TRP breakdown pathway in these cells [75]. The stimulation of IDO via FcεRI restricted inflammatory responses resulting from allergies [84]. The specific communication of nitric oxide (NO∙) with IDO1 could be significant since a higher production of NO∙ has been described in patients with allergic rhinitis and asthma. Significantly, NO∙ overwhelms the movement of IDO1, which could elucidate the greater TRP points [85]. Furthermore, IDO appears to play a role in the effectiveness of allergen immunotherapy. Tolerance stimulation against allergens is incompletely facilitated via IDO stimulation throughout SIT [86]. The creation of TRP products moderately than TRP scarcity appears to create a tolerance to allergens [86]. Therefore, IDO stimulation appears to be applicable throughout immunotherapy to make TRP products, which will then cause tolerance against the stimulation of airway inflammation due to allergy and help tolerance stimulation regarding Th2-related allergic airway inflammation and the suppression of eosinophilia [87].

Animal and in-vitro studies of IDO in allergic diseases

The role of TRP has extensive immunologic value, and IDO was first separated from rabbits in 1967 [88], and it became quickly obvious that its stimulation helps the mechanism of resistance to microbes. Various studies proving IDO as a proinflammatory enzyme in allergic conditions have been done in IDO knock-out mice [52]. In-vitro, it looks obvious that the lack of TRP definitely motivates the general control nonderepressible 2 (GCN2) kinase in T cells of murine and humans, which results in a pause in the G2 phase of the T-cell subdivision and T-cell suppression [53]. Additionally, a particular blend of TRP products can prevent anti-CD3 antibody-stimulated T-cell propagation and can prompt in-vitro T-cell death [55, 89]. The mixture of little TRP amounts and definite TRP products in-vitro results in the production of Tregs from naive T cells [90]. Adding exogenous KYN metabolites to numerous different cells of the immune system indicates that KYN products can optionally prevent dynamic T, B, and NK cells at additional physiologically-related TRP amounts than the TRP diminution theory would suggest [55, 91]. In addition, in pDCs extracted from murine that treated to TGFβ, this enzyme is capable of generating a cellular indication for continuing immune tolerance through the production of Tregs from CD4+ T-cells [24]. Similarly, Mellor and Munn’s theory (in-vitro) indicates that KYN encourages the conversion of naive CD4+ T-cells into Tregs that have an important immunosuppressive role [53]. Meanwhile, IDO-stimulated Treg propagation overpowers Th1 and Th2 cells, thus preventing an intense immune response. Xu et al. have suggested that throughout the sequence of a Th1-related response, the death of Th1 cells is favorably prompted. This is different from a Th2-related immune response, where the Th2 cells are targeted via the KYN-IDO pathway [41] (Table 1).

Table 1 In vitro and animal studies of IDO
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The human clinical trial of IDO in allergic diseases

Human studies have established that STI caused by grass pollen or house dust mites allergy contains improved amounts of Treg1 cells that mainly produce IL-10 [100] (Table 2). Firstly, a role of the TRP breakdown pathway in allergic disorders was suggested according to the results of a suppressive subtractive hybridization archive that was shown in high-affinity IgE receptor (FcεRI)-stimulated and unstimulated monocyte cells from a clinically healthy person with atopic family history and numerous sensitizations to shared aeroallergens [75]. This impact is possibly linked to dynamic IDO stimulation and IL-10 production via the activation of Treg throughout immunotherapy in these individuals. In contrast to inflammation due to allergy, particular IgE levels in the blood appear not to be affected by the stimulation of the TRP degradation pathway during SIT in mouse studies [87].

Table 2 Human trials studies of IDO
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Some of the robust human data for the role of IDO are connected to clinical experiments of specific immunotherapy (SIT) [84]. Primary outcomes from SIT trials confirmed advanced TRP degradation throughout the treatment [75]. IDO has consequently been confirmed to be partially accountable for tolerance stimulation throughout SIT, with KYN products facilitating this influence as opposed to TRP reduction [105, 106]. In contrast, human myeloid dendritic cells (mDCs) have an amplified ability to prompt CD4+CD25−Foxp3− T cells to Tregs with suppressive action [55]. In addition, amplified TRP catabolite levels in low or normal TRP conditions do not change the stimulatory role of human mDCs in-vitro [107].

It has also been found that the expression of IDO is inhibited by Th2 cytokines, such as IL-4 and IL-13, which are well known for their critical role in prompting, preserving, and magnifying inflammatory allergic inflammation [108]. It is imaginable that IDO stimulation throughout SIT produces controlling ILT3+ILT4+ DCs via TRP deficiency, which in turn prompts Tregs from CD4+CD25− effector T cells [90].

In-vitro, once FceRI+ monocytes (MONs) from asymptomatic atopic individuals are motivated for 24 h, these cells gain the capability to suppress T-cell propagation, depending on their expression of IDO and the breakdown of TRP [109]. By assessing the concentrations of KYN and TRP in the plasma, in aeroallergen-sensitized asymptomatic atopic individuals, there was a meaningfully greater universal action of IDO as well as amplified plasma concentrations of IL-10 during allergen season than off-season and symptomatic atopic persons. Consequently, improved general IDO activity may contribute to the control of allergic T-cell reactions and could be involved in the conservation of a state of clinical unresponsiveness regardless of sensitization.

Conclusion

IDO plays various roles in different diseases, including allergic diseases. Most studies confirm that IDO acts as an immunosuppressive, tolerogenic enzyme to decrease inflammation due to allergic disorders, with the stimulation of the IDO-KYN pathway, subsequent reduction of TRP, and promotion in KYN products. In the allergic situation, this enzyme is triggered in reaction to allergen-stimulated immune activation, with the subsequent production of KYN and their products, and the stimulation of tolerance to different allergens. The stimulation of the role of IDO and/or reducing the overall TRP concentrations via the induction of cells of the immune system might be of therapeutic benefit in allergic disorders. Additional studies are essential to determine how each of the KYN products acts to create tolerance against numerous allergens.