The Immunoregulatory Enzyme IDO Paradoxically Drives B Cell-Mediated Autoimmunity

The Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2009; 182(12):7509-17. DOI: 10.4049/jimmunol.0804328
Source: PubMed


Rheumatoid arthritis (RA) is a chronic and debilitating inflammatory autoimmune disease of unknown etiology. As with a variety of autoimmune disorders, evidence of elevated tryptophan catabolism has been detected in RA patients indicative of activation of the immunomodulatory enzyme IDO. However, the role that IDO plays in the disease process is not well understood. The conceptualization that IDO acts solely to suppress effector T cell activation has led to the general assumption that inhibition of IDO activity should exacerbate autoimmune disorders. Recent results in cancer models, however, suggest a more complex role for IDO as an integral component of the inflammatory microenvironment necessary for supporting tumor outgrowth. This has led us to investigate the involvement of IDO in the pathological inflammation associated with RA. Using the K/BxN murine RA model and IDO inhibitor 1-methyl-tryptophan, we found that inhibiting IDO activity had the unexpected consequence of ameliorating, rather than exacerbating arthritis symptoms. 1-Methyl tryptophan treatment led to decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course. This alleviation of arthritis was not due to an altered T cell response, but rather resulted from a diminished autoreactive B cell response, thus demonstrating a previously unappreciated role for IDO in stimulating B cell responses. Our findings raise the question of how an immunosuppressive enzyme can paradoxically drive autoimmunity. We suggest that IDO is not simply immunosuppressive, but rather plays a more complex role in modulating inflammatory responses, in particular those that are driven by autoreactive B cells.

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Available from: George C Prendergast, Oct 01, 2015
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    • "Moreover, a lot of studies underline the neuroprotective properties of KYNA in animals with experimental brain injury (Darlington et al. 2007; Gellért et al. 2013; Sas et al. 2008). KYNA production is also elevated during a bacterial or viral inflammation, an autoimmune disease and after a severe trauma (Forrest et al. 2006; Hartai et al. 2007; Scott et al. 2009; Zeden et al. 2010). Increases in plasma tryptophan metabolites have also been observed in patients undergoing elective abdominal or cardiac surgery (Forrest et al. 2011; Marfella et al. 1999). "
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    ABSTRACT: Increases in plasma kynurenic acid (KYNA) concentration relate to the severity of inflammation. The aim of this study was to analyse changes in plasma KYNA concentration and neutrophil/lymphocyte ratio (NLR) in cardiac surgery patients. Additionally, the effect of anaesthesia was analysed. Adult cardiac surgery patients under intravenous general anaesthesia were studied. Additionally, some patients received sevoflurane (SEV) prior to cardiopulmonary bypass. Plasma KYNA concentration and NLR were measured before anaesthesia, just after surgery and on postoperative days 1, 2 and 3. Patients were assigned to two groups: patients who did not receive SEV (NonSEV group) and patients who received SEV (SEV group). Forty-three patients were studied. Twenty-four of them received SEV. KYNA increased immediately after surgery and remained elevated through postoperative day 3 in the NonSEV group, whereas it was similar to the preoperative concentration in the SEV group. NLR increased immediately after surgery in both groups, and higher values were noted in the NonSEV group than in the SEV group at postoperative days 2 and 3. Plasma KYNA concentration correlated with NLR in the NonSEV group. Cardiac surgery caused an increase in NLR. Plasma KYNA increased in the NonSEV group and correlated with NLR. Administration of SEV inhibited the increase in KYNA, most likely due to its anti-inflammatory properties.
    Archivum Immunologiae et Therapiae Experimentalis 09/2014; 63(2). DOI:10.1007/s00005-014-0312-z · 3.18 Impact Factor
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    • "In contrast to studies in CIA, studies in the K/BxN model of RA showed that administration of 1-MT resulted in amelioration of arthritis due to a reduced level of autoreactive B cell activity.26 Further analysis revealed that the principal effect of 1-MT was to inhibit the ability of autoreactive B cells to differentiate into autoantibody-secreting cells, but did not influence their initial activation or survival.27 "
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    ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting step along the kynurenine pathway and is thought to play a key role in immune homeostasis through depletion of tryptophan and accumulation of kynurenines. In this review we summarize recent research into the possibility of harnessing the IDO pathway for the therapy of rheumatoid arthritis. Inhibition of IDO activity, or knockout of the gene encoding IDO, was shown to cause an increase in the severity of collagen-induced arthritis, an animal model of rheumatoid arthritis. The increased severity of disease was associated with elevated numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. In another study, analysis of the kinetics of expression of downstream kynurenine pathway enzymes during the course of arthritis revealed a potential role for tryptophan metabolites in resolution of arthritis. Furthermore, the therapeutic administration of L-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxy-anthranilic acid) significantly reduced both clinical and histological progression of experimental arthritis. These findings raise the possibility of exploiting the IDO pathway for the therapy of autoimmune disease.
    International Journal of Tryptophan Research 07/2013; 6(Suppl 1):67-73. DOI:10.4137/IJTR.S11737
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    • "Although the immune suppressive role of IDO has been generally accepted, increasing amounts of data suggest that IDO serves more than one function in the immune system [34], [35]. Inhibition of IDO activity in the K/BxN murine rheumatoid arthritis model resulted in amelioration rather than exacerbation of the arthritic symptoms with decreased autoantibody titers, reduced levels of inflammatory cytokines, and an attenuated disease course [36]. Specifically, IDO−/− mice and IDO inhibitor (1-methyl-tryptophan)-treated mice have decreased production of proinflammatory cytokines and increased survival from endotoxin shock [37], and IDO activity in bacteremic patients correlates with disease severity and case fatality [38]. "
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    ABSTRACT: Due to its strong immune stimulatory effects through TLR9, CpG-containing oligodeoxynucleotides (CpG ODN) have been tested in multiple clinical trials as vaccine adjuvant for infectious diseases and cancer. However, immune suppression induced by systemic administration of CpGs has been reported recently. In this study, we evaluated the impact of CpGs in an acute rickettsiosis model. We found that systemic treatment with type B CpG (CpG-B), but not type A CpG (CpG-A), at 2 days after sublethal R. australis infection induced mouse death. Although wild-type (WT) B6 and IDO(-/-) mice showed similar survival rates with three different doses of R. australis infection, treatment with CpG-B after sublethal infection consistently induced higher mortality with greater tissue bacterial loads in WT but not IDO(-/-) mice. Also, CpG-B treatment promoted the development of higher serum concentrations of proinflammatory cytokines/chemokines through IDO. Furthermore, while T cell-mediated immune responses enhanced by CpG-B were independent of IDO, treatment with CpG-B promoted T cell activation, PD-1 expression and cell apoptosis partially through IDO. A depletion study using anti-mPDCA-1 mAb indicated that plasmacytoid dendritic cells (pDC) were not required for CpG-B-induced death of R. australis-infected mice. Additionally, the results in iNOS(-/-) mice suggested that nitric oxide (NO) was partially involved in CpG-B-induced death of R. australis-infected mice. Surprisingly, pre-treatment with CpG-B before administration of a lethal dose of R. australis provided effective immunity in WT, IDO(-/-) and iNOS(-/-) mice. Taken together, our study provides evidence that CpGs exert complex immunological effects by both IDO-dependent and -independent mechanisms, and that systemic treatment with CpGs before or after infection has a significant and distinct impact on disease outcomes.
    PLoS ONE 03/2012; 7(3):e34062. DOI:10.1371/journal.pone.0034062 · 3.23 Impact Factor
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