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1.
Arthritis Rheumatol ; 68(11): 2740-2751, 2016 11.
Article in English | MEDLINE | ID: mdl-27159593

ABSTRACT

OBJECTIVE: In lupus nephritis, tubulointerstitial inflammation (TII) is associated with in situ adaptive immune cell networks that amplify local tissue damage. Since conventional therapy appears ineffective for severe TII, and these patients often progress to renal failure, understanding in situ mechanisms might reveal new therapeutic targets. This study was undertaken to assess whether dysregulated apoptotic regulators maintain local adaptive immunity and drive inflammation in TII. METHODS: This study utilized novel computational approaches that, when applied to multicolor confocal images, quantified apoptotic regulator protein expression in selected lymphocyte subsets. This approach was validated using laser-capture microdissection (LCM) coupled to quantitative polymerase chain reaction (qPCR). Furthermore, the consequences of dysregulated apoptotic mediator expression were explored in a murine model of lupus nephritis. RESULTS: Analyses of renal biopsy tissue from patients with lupus nephritis and those with mixed cellular renal allograft rejection revealed that the B cell lymphoma 2 protein (Bcl-2) was frequently expressed in infiltrating lymphocytes, whereas expression of myeloid cell leukemia 1 was low. In contrast, the reciprocal pattern of expression was observed in tonsil germinal centers. These results were consistent with RNA expression data obtained using LCM and qPCR. Bcl-2 was also highly expressed in tubulointerstitial infiltrates in (NZB × NZW)F1 (NZB/NZW) mice. Furthermore, treatment of NZB/NZW mice with ABT-199, a selective oral inhibitor of Bcl-2, prolonged survival and prevented proteinuria and development of TII in a lupus prevention model. Interestingly, glomerular immune complexes were partially ameliorated by ABT-199 treatment, and serum anti-double-stranded DNA antibody titers were unaffected. CONCLUSION: These data demonstrate that Bcl-2 is an attractive therapeutic target in patients with lupus nephritis who manifest TII.


Subject(s)
Apoptosis , Lupus Nephritis/metabolism , Lymphocytes/metabolism , Nephritis, Interstitial/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Adaptive Immunity/immunology , Animals , Antigen-Antibody Complex/drug effects , Antigen-Antibody Complex/immunology , Antigen-Antibody Complex/metabolism , Bcl-2-Like Protein 11/genetics , Bcl-2-Like Protein 11/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Female , Germinal Center/metabolism , Graft Rejection/immunology , Graft Rejection/metabolism , Humans , Image Processing, Computer-Assisted , Immunohistochemistry , Inflammation , Kidney/drug effects , Kidney/immunology , Kidney/metabolism , Kidney Glomerulus/drug effects , Kidney Glomerulus/immunology , Kidney Glomerulus/metabolism , Kidney Transplantation , Laser Capture Microdissection , Lupus Nephritis/immunology , Lymphocytes/immunology , Mice , Mice, Inbred NZB , Microscopy, Confocal , Microscopy, Fluorescence , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Nephritis, Interstitial/immunology , Palatine Tonsil , Polymerase Chain Reaction , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/genetics , Sulfonamides/pharmacology
2.
Am J Pathol ; 170(1): 110-25, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17200187

ABSTRACT

The transforming growth factor (TGF)-beta-inducible integrin alpha v beta6 is preferentially expressed at sites of epithelial remodeling and has been shown to bind and activate latent precursor TGF-beta. Herein, we show that alpha v beta6 is overexpressed in human kidney epithelium in membranous glomerulonephritis, diabetes mellitus, IgA nephropathy, Goodpasture's syndrome, and Alport syndrome renal epithelium. To assess the potential regulatory role of alpha v beta6 in renal disease, we studied the effects of function-blocking alpha v beta6 monoclonal antibodies (mAbs) and genetic ablation of the beta6 subunit on kidney fibrosis in Col4A3-/- mice, a mouse model of Alport syndrome. Expression of alpha v beta6 in Alport mouse kidneys was observed primarily in cortical tubular epithelial cells and in correlation with the progression of fibrosis. Treatment with alpha v beta6-blocking mAbs inhibited accumulation of activated fibroblasts and deposition of interstitial collagen matrix. Similar inhibition of renal fibrosis was observed in beta6-deficient Alport mice. Transcript profiling of kidney tissues showed that alpha v beta6-blocking mAbs significantly inhibited disease-associated changes in expression of fibrotic and inflammatory mediators. Similar patterns of transcript modulation were produced with recombinant soluble TGF-beta RII treatment, suggesting shared regulatory functions of alpha v beta6 and TGF-beta. These findings demonstrate that alpha v beta6 can contribute to the regulation of renal fibrosis and suggest this integrin as a potential therapeutic target.


Subject(s)
Antigens, Neoplasm/biosynthesis , Integrins/biosynthesis , Nephritis, Hereditary/metabolism , Animals , Antibodies, Blocking/immunology , Antibodies, Blocking/pharmacology , Antigens, Neoplasm/immunology , Disease Models, Animal , Extracellular Matrix/drug effects , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Fibrosis , Humans , Immunohistochemistry , Integrins/antagonists & inhibitors , Integrins/immunology , Kidney/metabolism , Kidney/pathology , Mice , Mice, Knockout , NIH 3T3 Cells , Nephritis, Hereditary/drug therapy , Nephritis, Hereditary/etiology , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism , Up-Regulation
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