Date: Monday, October 22, 2018
Session Type: ACR Concurrent Abstract Session
Session Time: 4:30PM-6:00PM
Indoleamine-2,3-dioxygenase (IDO) is a tryptophan catabolizing enzyme which plays a role in immune regulation and in the pathogenesis of autoimmune disorders. Increased IDO activity was reported in systemic lupus erythematosus (SLE). The tolerogenic peptide, hCDR1, ameliorates lupus manifestations via the immunomodulation of cytokines and the induction of FOXP3 expressing regulatory T cells . The aim of this study has been to determine the effect of hCDR1 on IDO gene expression in SLE.
(NZBxNZW)F1 female mice with established SLE manifestations were treated (10 weekly subcutaneously injections) with hCDR1, control peptide or vehicle alone. The effects on anti-dsDNA antibody titers, proteinuria levels and kidney immunohistology were assessed. Splenocytes were obtained for gene expression studies. Nine Lupus patients were treated for 26 weeks with hCDR1 (5) or vehicle (4) in a Phase II clinical trial by weekly subcutaneous injections . Blood samples were collected, before and after treatment, in PAXgene tubes and frozen until mRNA isolation.Peripheral blood lymphocytes (PBL) of 16 lupus patients and 6 healthy controls were incubated for 48 hours with hCDR1, control peptide or medium alone prior to gene expression assays. Gene expression of IDO and FOXP3 was determined by real-time RT-PCR.
Treatment of (NZBxNZW)F1 SLE afflicted mice with hCDR1 down-regulated significantly IDO gene expression (72.4% and 71% inhibition compared to vehicle, p= 0.0001 and to control peptide p=0.05, respectively). This was associated with a significant reduction of anti-dsDNA antibody titers, proteinuria levels and glomerular immune complex deposits. Similarly, a significant reduction in IDO gene expression was determined in samples of hCDR1 treated lupus patients (57.4% inhibition compared to pretreatment levels, p=0.0046). No inhibition of IDO expression was observed in the vehicle treated patients. In agreement, as previously reported, treatment with hCDR1, but not with the vehicle, resulted in a significant decrease of disease activity . Further, hCDR1 significantly reduced, in vitro, IDO gene expression in PBL of lupus patients (p=0.00017and p=0.021 compared to medium and to control peptide, respectively). In contrast, hCDR1 up-regulated by more than two folds the expression of FOXP3 gene in PBL of the same lupus patients. hCDR1 did not affect the expression of the latter genes in PBL of healthy controls.
hCDR1 significantly down-regulated IDO gene expression in SLE affected mice and in lupus patients (treated in vivo as well as in vitro). This effect is specific because it was not observed in healthy donors or following treatment with the control peptide. The reduction of IDO gene expression was associated with the beneficial effects of hCDR1. We reported previously that hCDR1 affects various immune pathways and cell types, most importantly, FOXP3 expressing functional T regulatory cells . Our results suggest that the up-regulation of FOXP3 in lupus is not driven by IDO but it is rather controlled by other pathways and cytokines (e.g. TGF-b) that were shown to be induced by hCDR1.
 Journal of Autoimmunity 54, (2014) 60-71.
To cite this abstract in AMA style:Sthoeger Z, Sharabi A, zinger H, asher I, mozes E. Indoleamine-2,3-Dioxygenase in Murine and Human Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/indoleamine-23-dioxygenase-in-murine-and-human-systemic-lupus-erythematosus/. Accessed December 3, 2021.
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