Animal Models of SLE

Hahn, Bevra H.; Kono, Dwight H.

doi:10.1016/b978-1-4377-1893-5.00017-0

Cited by 12 publications

(12 citation statements)

References 661 publications

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“…Because NZB/NZW mice develop renal failure with IgG and C3 deposition as well as acute and chronic pathologic changes (), we examined renal specimens from 35‐week‐old control and treated mice. Both laquinimod and MMF reduced deposition of IgG and C3 in glomeruli compared to that in control mouse kidneys (further data available upon request from the corresponding author).…”

Section: Resultsmentioning

confidence: 99%

Laquinimod Delays and Suppresses Nephritis in Lupus‐Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells

Lourenço

Wong

Hahn

et al. 2014

Arthritis & Rheumatology

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Objective. Lupus nephritis depends on autoantibody deposition and activation of multiple immune cell types that promote kidney inflammation, including lymphocytes and monocyte/macrophages. Laquinimod, currently in clinical trials for multiple sclerosis and lupus nephritis, reduces infiltration of inflammatory cells into the spinal cord in experimental autoimmune encephalomyelitis. Activated monocyte/macrophages infiltrate the kidneys during nephritis in systemic lupus erythematosus (SLE). We undertook this study to determine whether using laquinimod to reduce monocyte/macrophage-driven tissue damage as well as to alter lymphocytes in SLE nephritis could have greater therapeutic benefit than current treatments that primarily affect lymphocytes, such as mycophenolate mofetil (MMF).Methods. To test laquinimod efficacy, we used the (NZB ؋ NZW)F1 mouse model of SLE, in which disease manifests as nephritis. Preventive and therapeutic studies were performed to determine whether laquinimod could prevent or delay nephritis, as measured by proteinuria, serum creatinine, survival, and renal pathology. Spleen and kidney leukocyte populations and suppression assays were analyzed by flow cytometry.Results. Laquinimod prevented or delayed lupus manifestations at levels equal to or better than MMF. Laquinimod treatment was associated with reduced numbers of monocyte/macrophages, dendritic cells, and lymphocytes, as well as with induction of myeloidderived suppressor cells in spleens and kidneys. Laquinimod suppressed macrophage-secreted tumor necrosis factor ␣ and induced production of interleukin-10 (IL-10). In addition, laquinimod suppressed interferon-␥ and IL-17 production by lymphocytes and down-regulated expression of activation/ costimulatory markers on antigen-presenting cells.Conclusion. The effects of laquinimod on myeloid and lymphoid cells may contribute to improvements in (NZB ؋ NZW)F1 mouse survival, proteinuria, and glomerulonephritis. Future development of laquinimod as a therapeutic agent for lupus nephritis is promising.

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Section: Resultsmentioning

confidence: 99%

Laquinimod Delays and Suppresses Nephritis in Lupus‐Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells

Lourenço

Wong

Hahn

et al. 2014

Arthritis & Rheumatology

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“…CD4 + T cells also contribute to the disease of NZB mice because of the types of MHC-II molecules expressed by these mice. Naturally, hemolytic anemia instead of lupus is a major cause of death in NZB mice 26 . NZB/W F1 is the only heterozygous strain that inherits disease-related gene loci from both NZW and NZB mice and develops severe lupus symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…Lupus-prone mice, such as NZB, NZW and NZB/W F1 mice, exhibit higher spleen pDC numbers than C57BL/6 mice 24 25 . Moreover, NZB mice show increased IFNα secretion following in vivo CpG injection 26 . Hence, we hypothesize that pDCs may represent an important IFNα source in both SLE patients and lupus-prone mice.…”

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confidence: 99%

Phenotypic and functional alterations of pDCs in lupus-prone mice

Zhou

Xiao

et al. 2016

Sci Rep

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Plasmacytoid dendritic cells (pDCs) were considered to be the major IFNα source in systemic lupus erythematosus (SLE) but their phenotype and function in different disease status have not been well studied. To study the function and phenotype of pDCs in lupus-prone mice we used 7 strains of lupus-prone mice including NZB/W F1, NZB, NZW, NZM2410, B6.NZMSle1/2/3, MRL/lpr and BXSB/Mp mice and C57BL/6 as control mice. Increased spleen pDC numbers were found in most lupus mice compared to C57BL/6 mice. The IFNα-producing ability of BM pDCs was similar between lupus and C57BL/6 mice, whereas pDCs from the spleens of NZB/W F1 and NZB mice produced more IFNα than pDCs from the spleens of C57BL/6 mice. Furthermore, spleen pDCs from MRL-lpr and NZM2410 mice showed increased responses to Tlr7 and Tlr9, respectively. As the disease progressed, IFN signature were evaluated in both BM and spleen pDC from lupus prone mice and the number of BM pDCs and their ability to produce IFNα gradually decreased in lupus-prone mice. In conclusion, pDC are activated alone with disease development and its phenotype and function differ among lupus-prone strains, and these differences may contribute to the development of lupus in these mice.

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“…Thus, the systemic lupus-like features observed in scurfy mice appear to be a consequence of Treg dysfunction and uncontrolled CD4 + T eff cell expansion, and, interestingly, a deficiency in Treg number and function has also repeatedly been postulated in human and murine SLE [ 21 , 51 , 52 ]. Therefore, the finding that scurfy mice present with many important characteristics of SLE supports the idea of a pathogenic role of Treg deficiency in this autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

Hadaschik¹,

Wei²,

Leiss³

et al. 2015

Arthritis Res Ther

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IntroductionScurfy mice are deficient in regulatory T cells (Tregs), develop a severe, generalized autoimmune disorder that can affect almost every organ and die at an early age. Some of these manifestations resemble those found in systemic lupus erythematosus (SLE). In addition, active SLE is associated with low Treg numbers and reduced Treg function, but direct evidence for a central role of Treg malfunction in the pathophysiology of lupus-like manifestations is still missing. In the present study, we characterize the multiorgan pathology, autoantibody profile and blood count abnormalities in scurfy mice and show their close resemblances to lupus-like disease.MethodsScurfy mice have dysfunctional Tregs due to a genetic defect in the transcription factor Forkhead box protein 3 (Foxp3). We analyzed skin, joints, lung and kidneys of scurfy mice and wild-type (WT) controls by conventional histology and immunofluorescence (IF) performed hematological workups and tested for autoantibodies by IF, immunoblotting and enzyme-linked immunosorbent assay. We also analyzed the intestines, liver, spleen and heart, but did not analyze all organs known to be affected in scurfy mice (such as the testicle, the accessory reproductive structures, the pancreas or the eyes). We transferred CD4+ T cells of scurfy or WT mice into T cell-deficient B6/nude mice.ResultsWe confirm previous reports that scurfy mice spontaneously develop severe pneumonitis and hematological abnormalities similar to those in SLE. We show that scurfy mice (but not controls) exhibited additional features of SLE: severe interface dermatitis, arthritis, mesangioproliferative glomerulonephritis and high titers of anti-nuclear antibodies, anti-double-stranded DNA antibodies, anti-histone antibodies and anti-Smith antibodies. Transfer of scurfy CD4+ T cells (but not of WT cells) induced autoantibodies and inflammation of lung, skin and kidneys in T cell-deficient B6/nude mice.ConclusionOur observations support the hypothesis that lupus-like autoimmune features develop in the absence of functional Tregs.

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Animal Models of SLE

Cited by 12 publications

References 661 publications

Laquinimod Delays and Suppresses Nephritis in Lupus‐Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells

Laquinimod Delays and Suppresses Nephritis in Lupus‐Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells

Phenotypic and functional alterations of pDCs in lupus-prone mice

Regulatory T cell-deficient scurfy mice develop systemic autoimmune features resembling lupus-like disease

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