Severe glomerulonephritis involves cell necrosis as well as NETosis, programmed neutrophil death leading to expulsion of nuclear chromatin and neutrophil extracellular traps (NETs). Histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells. This was prevented by histone-neutralizing agents anti-histone IgG, activated protein C and heparin. Histone toxicity on glomeruli was TLR2/4-dependent. Anti-GBM glomerulonephritis involved NET formation and vascular necrosis. Pre-emptive anti-histone IgG administration significantly reduced all aspects of glomerulonephritis, including vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment and activation of glomerular leukocytes and glomerular crescent formation. Subjects with established glomerulonephritis treated with anti-histone IgG, recombinant activated protein C, or heparin all abrogated severe glomerulonephritis suggesting that histone-mediated glomerular pathology is a subsequent, not initial event in necrotizing glomerulonephritis. Neutralizing extracellular histones is therapeutic in severe experimental glomerulonephritis.

Immunomedics, Inc.

Anti-histone therapy for vascular necrosis in severe glomerulonephritis

Compounds of a histone deacetylase inhibitor. The compounds are capable of simultaneously stimulating epithelium regrowth, inhibiting cutaneous fibroblast proliferation, decreasing collagen deposit, suppressing fibrogenic growth factor and subsiding inflammatory cytokine, and are useful inhibiting the main features of radiation cutaneous syndrome. Results include a decrease in skin swelling, promotion of epithelium healing, and prevention of cutaneous fibrosis, ulceration and necrosis. The present invention provides methods of treating, preventing or ameliorating radiation-induced skin damage by administering a therapeutically effective amount of a histone deacetylase inhibitor.

Methods for therapy of radiation cutaneous syndrome

The present invention provides compositions and methods for increasing therapeutic gain in radiotherapy and chemotherapy for proliferating malignant or nonmalignant disease to produce high probability of tumor control with low frequency of sequelae of therapy by administering a therapeutically effective amount of a histone deacetylase inhibitor. The compounds are capable of simultaneously stimulating the epithelium regrowth, inhibiting the fibroblast proliferation, decreasing the collagen deposit, suppressing the fibrogenic growth factor, subsiding the proinflammatory cytokine and modulating the expression of cell cycle genes, tumor suppressors and oncogenes, and are useful to increase the therapeutic gain in radiotherapy and chemotherapy, which results in decrease of skin swelling and inflammation, promotion of epithelium healing in mucosa and dermis, decrease of xerostomia, prevention/reduction of severity of plantar-palmar syndrome, prevention of tissue fibrosis, ulceration, necrosis and tumorigenesis, and increase of tumor growth inhibition and tumor therapy effectiveness.

histone/nekroz

Anti-histone therapy for vascular necrosis in severe glomerulonephritis

Methods for therapy of radiation cutaneous syndrome

Method for reducing radiation-induced normal tissue damage

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