VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation

Agents targeting the B7 family co-inhibitory receptors cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1), or its ligand (PD-L1), have a pivotal role in clinical practice. V-domain Ig suppressor of T-cell activation (VISTA) is a protein highly conserved between species, with a similar amino acid sequence to the B7 family members, characterized by a particularly structural homology to PD-1. It has been counted as an emerging target within the list of novel targetable immune checkpoints in oncology. Physiologically, VISTA exerts a regulatory function on the immune system at several levels, particularly by modulating T cells activation. Its altered activity plays a role in many autoimmune diseases, and its expression has been found to be prognostically implicated in different cancer types in preclinical models. We hereby present the main evidence on the value of VISTA as an immune checkpoint in solid and hematological malignancies. We also review its value as a potential target for cancer immunotherapy, by reporting the results of Phase I and II clinical trials assessing the use of drugs targeting VISTA. The complexity of its pathway, along with some unclear biological aspects concerning its molecular interactions, currently represent a limit to the applicability of VISTA as an effective biomarker for immunotherapy in oncology. A deeper characterization of this immune checkpoint may help defining its value within immune signatures of solid and hematological malignancies, and to design future therapeutic strategies.

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“…This suggests that VISTA may be a potential target in immune-complex mediated glomerulonephritis. 31 …”

Section: Physio(patho)logical Function Of Vista: In Vitro and In Vivo Modelsmentioning

confidence: 99%

VISTA: A Promising Target for Cancer Immunotherapy?

Tagliamento¹,

Agostinetto²,

Borea³

et al. 2021

ITT

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“…We have previously shown, using the same neutrophil-deficient mouse strain, that myeloid-specific Mcl1 is required in the nephrotoxic nephritis model. 12 In this previous study, there were fewer circulating neutrophils but no differences in circulating monocytes at any time point. These results suggested an essential role for neutrophils in the nephrotoxic nephritis model.…”

Section: Discussionmentioning

confidence: 65%

Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective

Flórez-Barrós

Bearder

Kull

et al. 2023

Kidney International

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“…However, the depleting antibody used (NIMP‐R14) would have also affected monocytes, so the relative importance of monocytes and neutrophils was not clear. We have shown that neutrophils are essential in the autologous nephrotoxic nephritis model of crescentic glomerulonephritis using mice with a genetic deficiency of neutrophils ( 16 ). Therefore, it seems likely that neutrophils are required in anti‐MPO vasculitis.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 3‐Kinase δ Deficiency Protects From Antimyeloperoxidase Vasculitis

Flórez-Barrós

Freeley

Tham

et al. 2022

Arthritis & Rheumatology

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Objective Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) is a systemic autoimmune disease in which glomerulonephritis is an important manifestation. Antibodies against myeloperoxidase (MPO) or proteinase 3 are thought to be important in pathogenesis. Phosphoinositide 3‐kinase δ (PI3Kδ) mediates a number of effects in lymphocytes, but its role in myeloid cell responses is less clear. Therefore, this study was undertaken to assess this in a preclinical model of glomerulonephritis induced by the transfer of antibodies to MPO. Methods D910A mice with inactive PI3Kδ were compared with wild‐type controls. Disease protocols allowed for a comparison of experimental groups in the setting of both mild and more severe disease. Adoptive transfer experiments were performed, with flow cytometric analysis of digested kidneys taken at the end of the experiment. Results With mild disease, D910A mice had fewer glomerular macrophages, fewer glomerular neutrophils, and reduced albuminuria compared with wild‐type controls. With more severe disease, they also had fewer glomerular crescents and lower serum creatinine levels, indicating protection from acute kidney injury. Adoptive transfer experiments showed a defect in the recruitment of D910A monocytes to the diseased kidney. Conclusion Mice with inactive PI3Kδ were protected from anti‐MPO vasculitis. This is due to cell intrinsic defect in the recruitment of monocytes to the kidney. These findings suggest that PI3Kδ is a potential therapeutic target in AAV.

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VISTA deficiency protects from immune complex-mediated glomerulonephritis by inhibiting neutrophil activation

Cited by 7 publications

References 32 publications

VISTA: A Promising Target for Cancer Immunotherapy?

VISTA: A Promising Target for Cancer Immunotherapy?

Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective

Phosphatidylinositol 3‐Kinase δ Deficiency Protects From Antimyeloperoxidase Vasculitis

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