Etiology and pathogenesis of a spontaneous lupus-like syndrome in mice

Dixon, Frank J.; Andrews, Brian S.; Eisenberg, Robert A.; McConahey, Patricia J.; Theofilopoulos, Argyrios N.; Wilson, Curtis B.

doi:10.1002/art.1780210909

Cited by 76 publications

(60 citation statements)

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“…Increased IDO in these situations acts to attenuate harmful inflammation, as shown by the marked exacerbation of disease in all of these models when IDO is inhibited. Lupus-prone Murphy Roths large (MRL) lpr/lpr mice show a prolonged period of chronic inflammation and autoimmunity before the development of overt disease (23)(24)(25)(26). We asked whether IDO function was involved in limiting development of systemic autoimmune disease in MRL lpr/lpr mice.…”

Section: Ido Regulates Spontaneous Autoimmune Disease Progression Inmentioning

confidence: 99%

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Ravishankar

Liu²,

Shinde³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

168

210

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Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.inflammation | macrophage M acrophages (MΦ) are innate scavenging cells that are important in maintenance of tolerance to self. Mechanistically, it is unknown how MΦs contribute to self-tolerance although it is evident that clearance is necessary and must lead to regulation rather than adaptive immunity. In this vein it has been shown that interaction of apoptotic cells with MΦs results in the induction of an anti-inflammatory response dominated by TGF-β, which suppresses proinflammatory cytokine production (1, 2). However, the molecular mechanisms by which capture of apoptotic cells trigger immune suppression in vivo is unknown. Moreover, known mechanisms, such as exposure of phosphatidyl serine and TGF-β production, do not explain how tolerance is maintained at the molecular level.Apoptotic cells in circulation are trapped and removed in the marginal zone (MZ) of the spleen (3). The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4-6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7). Similarly, in related studies deletion of MARCO + and MOMA-1 + MZMs retarded the clearance of apoptotic material and abrogated tolerance to apoptotic cell-associated antigens in a mouse model of experimental autoimmune encephalomyelitis (8). Thus, defective MZM-mediated apoptotic cell capture and removal appears to have sig...

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Section: Ido Regulates Spontaneous Autoimmune Disease Progression Inmentioning

confidence: 99%

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Ravishankar

Liu²,

Shinde³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

168

210

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“…Anti-product antibodies were detected during the period of rapid clearance in animals treated with Ab-01 (Suppl. 22,23 and appeared to have faster onset and/or higher frequency of anti-Ab-01 antibodies (detected in 100% of tested samples), compared to healthy mice (detected in ∼37-75% of tested samples) (Suppl. Table 1).…”

Section: Isolation and In Vitro Characterization Of Optimized Anti-ilmentioning

confidence: 99%

In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus

Vugmeyster

Guay

Szklut

et al. 2010

mAbs

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“…T cells was observed [7]. Hart et al [8] reported that mouse lymphocytes cultured with syngeneic vascular smooth muscle cells induced vasculitis after an adoptive transfer.…”

Section: Introductionmentioning

confidence: 99%

A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice

Sumita

Ozaki

Okazaki

et al. 1996

Clinical and Experimental Immunology

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SUMMARYWe established a T cell line, MV1, specific for rat vascular smooth muscle antigen from the regional lymph nodes of immunized MRL/Mp-/ mice. Adoptive transfer of MV1 T cells induced vasculitis lesions in the lungs of the syngeneic recipient mice pre-treated with cyclophosphamide. Flow cytometric analysis showed that MV1 was a CD4T cell line. The T cells proliferated in the presence of the vascular smooth muscle antigen and mitomycin C-treated syngeneic spleen cells. The cross experiments using an ovalbumin-specific T cell line demonstrated that MV1 was specific for vascular smooth muscle antigen. The antigen-specific proliferation of MV1 was CD4-dependent, which was consistent with the flow cytometric analysis. In addition, MV1 T cells, upon activation with anti-CD3 antibody or antigen-specific activation, killed A20.

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Etiology and pathogenesis of a spontaneous lupus-like syndrome in mice

Cited by 76 publications

References 0 publications

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

In vitro potency, pharmacokinetic profiles and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus

A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice

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