Bcl-2 as a Therapeutic Target in Human Tubulointerstitial Inflammation

Arthritis Rheumatol. 2016 Nov;68(11):2740-2751. doi: 10.1002/art.39744.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Antigen-Antibody Complex / drug effects
  • Antigen-Antibody Complex / immunology
  • Antigen-Antibody Complex / metabolism
  • Apoptosis*
  • 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
  • Lupus Nephritis / metabolism*
  • Lymphocytes / immunology
  • Lymphocytes / metabolism*
  • 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
  • Nephritis, Interstitial / metabolism*
  • Palatine Tonsil
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Sulfonamides / pharmacology


  • Antigen-Antibody Complex
  • BCL2 protein, human
  • Bcl-2-Like Protein 11
  • Bridged Bicyclo Compounds, Heterocyclic
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • venetoclax