title: 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 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.
  
  
  
  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 IFNα, IFNγ, 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 IFNα signature, and supports a strategy of enhancement of the immunosuppressive activity of VISTA for the treatment of human lupus.
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ceeraz
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Petra A
authors.initials: PA
authors.lastname: Sergent
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Plummer
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Schned
authors.affiliation: ImmuNext, Inc., Lebanon, New Hampshire.
authors.forename: Dov
authors.initials: D
authors.lastname: Pechenick
authors.affiliation: Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Burns
authors.affiliation: Geisel School of Medicine at Dartmouth, and ImmuNext, Inc., Lebanon, New Hampshire.
authors.forename: Randolph J
authors.initials: RJ
authors.lastname: Noelle
mesh_terms: D000818:Animals; D005260:Female; D008181:Lupus Nephritis / Q000209:etiology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice
chemical_list: D008565:Membrane Proteins; C548983:Vsir protein, mouse