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VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis.

ABSTRACT: The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V-domain Ig-containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1?) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathway is a novel strategy for the treatment of human autoimmune disease, and therefore we undertook this study to determine the impact of VISTA genetic deficiency on lupus development in a lupus-prone mouse strain.To evaluate whether genetic deficiency of VISTA affects the development of lupus, we interbred VISTA-deficient mice with Sle1.Sle3 mice, a well-characterized model of systemic lupus erythematosus (SLE).We demonstrated that the development of proteinuria and glomerulonephritis in these mice, designated Sle1.Sle3 VISTA-/- mice, was greatly accelerated and more severe compared to that in Sle1.Sle3 and C57BL/6 VISTA-/- mice. Analysis of cells from Sle1.Sle3 VISTA-/- mice showed enhanced activation of splenic CD4+ T cells and myeloid cell populations. No increase in titers of autoantibodies was seen in Sle1.Sle3 VISTA-/- mice. Most striking was a significant increase in proinflammatory cytokines, chemokines, and interferon (IFN)-regulated genes associated with SLE, such as IFN?, IFN?, tumor necrosis factor, interleukin-10, and CXCL10, in Sle1.Sle3 VISTA-/- mice.This study demonstrates for the first time that loss of VISTA in murine SLE exacerbates disease due to enhanced myeloid and T cell activation and cytokine production, including a robust IFN? signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.

SUBMITTER: Ceeraz S

PROVIDER: S-EPMC5723399 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis.

Ceeraz Sabrina S Sergent Petra A PA Plummer Sean F SF Schned Alan R AR Pechenick Dov D Burns Christopher M CM Noelle Randolph J RJ

Arthritis & rheumatology (Hoboken, N.J.) 20170401 4

<h4>Objective</h4>The targeting of negative checkpoint regulators as a means of augmenting antitumor immune responses is now an increasingly used and remarkably effective approach to the treatment of several human malignancies. The negative checkpoint regulator VISTA (V-domain Ig-containing suppressor of T cell activation; also known as programmed death 1 homolog or as death domain 1α) suppresses T cell responses and regulates myeloid activities. We proposed that exploitation of the VISTA pathwa ...[more]

PMID: 27992697

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Project description:BackgroundThe purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model.MethodsFemale NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes.ResultsTreatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 microg/ml versus 1,036 microg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 microg/ml versus 614 microg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-gamma, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand.ConclusionAldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.

Project description:BackgroundOne of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ER? deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ER? deficiency would be similarly protective in the brain, and that ER? may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice.MethodsMRL/lpr ER?+/+ and ER?KO mice (n?=?46) were ovariectomized, received 17?-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting.ResultsMRL/lpr ER?KO mice (n?=?21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n?=?25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ER?KO mice. There were significant differences in NOR testing, particularly total exploration time, with ER? deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ER?KO mice, as evidenced by immunohistochemietry (IHC).ConclusionER? deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ER?KO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed.

Dataset Information

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis.

Publications

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis.

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