title: IDO1 Deficiency Does Not Affect Disease in Mouse Models of Systemic Juvenile Idiopathic Arthritis and Secondary Hemophagocytic Lymphohistiocytosis.
abstract: OBJECTIVE
  Indoleamine 2,3-dioxygenase-1 (IDO1) is an immune-modulatory enzyme that catalyzes the degradation of tryptophan (Trp) to kynurenine (Kyn) and is strongly induced by interferon (IFN)-γ. We previously reported highly increased levels of IFN-γ and corresponding IDO activity in patients with hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory syndrome. On the other hand, IFN-γ and IDO were low in patients with systemic juvenile idiopathic arthritis (sJIA), an autoinflammatory syndrome. As HLH can occur as a complication of sJIA, the opposing levels of both IFN-γ and IDO are remarkable. In animal models for sJIA and HLH, the role of IFN-γ differs from being protective to pathogenic. In this study, we aimed to unravel the role of IDO1 in the pathogenesis of sJIA and HLH.
  
  
  METHODS
  Wild-type and IDO1-knockout (IDO1-KO) mice were used in 3 models of sJIA or HLH: complete Freund's adjuvant (CFA)-injected mice developed an sJIA-like syndrome and secondary HLH (sHLH) was evoked by either repeated injection of unmethylated CpG oligonucleotide or by primary infection with mouse cytomegalovirus (MCMV). An anti-CD3-induced cytokine release syndrome was used as a non-sJIA/HLH control model.
  
  
  RESULTS
  No differences were found in clinical, laboratory and hematological features of sJIA/HLH between wild-type and IDO1-KO mice. As IDO modulates the immune response via induction of regulatory T cells and inhibition of T cell proliferation, we investigated both features in a T cell-triggered cytokine release syndrome. Again, no differences were observed in serum cytokine levels, percentages of regulatory T cells, nor of proliferating or apoptotic thymocytes and lymph node cells.
  
  
  CONCLUSIONS
  Our data demonstrate that IDO1 deficiency does not affect inflammation in sJIA, sHLH and a T cell-triggered cytokine release model. We hypothesize that other tryptophan-catabolizing enzymes like IDO2 and tryptophan 2,3-dioxygenase (TDO) might compensate for the lack of IDO1.
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Put
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Brisse
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Avau
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Maya
authors.initials: M
authors.lastname: Imbrechts
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Mitera
authors.affiliation: Laboratory of Molecular Immunology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Rik
authors.initials: R
authors.lastname: Janssens
authors.affiliation: Laboratory of Molecular Immunology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Proost
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Laboratory of Pediatric Immunology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Carine H
authors.initials: CH
authors.lastname: Wouters
authors.affiliation: Laboratory of Immunobiology, Rega-Institute for Medical Research, Department of Immunology and Microbiology, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology; D001171:Arthritis, Juvenile / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood*; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D005620:Freund's Adjuvant / Q000276:immunology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000473:pathology*; D055501:Macrophage Activation Syndrome / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D014366:Tryptophan Oxygenase / Q000378:metabolism
chemical_list: D016207:Cytokines; C583637:IDO1 protein, mouse; C586429:IDO2 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D005620:Freund's Adjuvant; D014366:Tryptophan Oxygenase