VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis

Objective 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...

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Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2017-04, Vol.69 (4), p.814-825
Main Authors: Ceeraz, Sabrina, Sergent, Petra A., Plummer, Sean F., Schned, Alan R., Pechenick, Dov, Burns, Christopher M., Noelle, Randolph J.
Format: Article
Language:English
Subjects:
Animals
Antitumor activity
Apoptosis
Autoantibodies
Autoimmune diseases
CD4 antigen
Cell activation
Chemokines
Chronic conditions
CXCL10 protein
Cytokines
Exploitation
Female
Glomerulonephritis
Homology
Immunoglobulins
Immunosuppressive agents
Inflammation
Interferon
Interleukins
Lupus
Lupus nephritis
Lupus Nephritis - etiology
Lymphocytes
Lymphocytes T
Medical treatment
Membrane Proteins - deficiency
Membrane Proteins - genetics
Mice
Nephritis
PD-1 protein
Proteinuria
Regulators
Rodents
Spleen
Systemic lupus erythematosus
T cell receptors
α-Interferon
γ-Interferon
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Summary:Objective 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 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. Methods 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). Results 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 IFNα, IFNγ, tumor necrosis factor, interleukin‐10, and CXCL10, in Sle1.Sle3 VISTA−/− mice. Conclusion 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 IFNα signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.
ISSN:2326-5191
2326-5205
DOI:10.1002/art.40020