Anti-tumor necrosis factor α treatment of interferon-α-induced murine lupus nephritis reduces the renal macrophage response but does not alter glomerular immune complex formation.
OBJECTIVE
To analyze the mechanism for the therapeutic effects of tumor necrosis factor α (TNFα) inhibition in a murine model of systemic lupus erythematosus.


METHODS
We used the (NZB × NZW)F(1)  (NZB/NZW) mouse model of interferon-α-induced lupus nephritis and treated mice with TNF receptor type II (TNFRII) Ig after TNFα expression was detected in the kidneys. Autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA), and autoantibody- forming cells were determined using an enzyme-linked immunospot assay. Activation of splenocytes was analyzed by flow cytometry. Kidneys were harvested and analyzed using flow cytometry, immunohistochemistry, ELISA, Western blotting, and real-time polymerase chain reaction.


RESULTS
TNFRII Ig treatment stabilized nephritis and markedly prolonged survival. Autoantibody production and systemic immune activation were not inhibited, but the renal response to glomerular immune complex deposition was attenuated. This was associated with decreases in renal production of chemokines, renal endothelial cell activation, interstitial F4/80(high)  macrophage accumulation, tubular damage, and oxidative stress. In contrast, perivascular lymphoid aggregates containing B cells, T cells, and dendritic cells accumulated unabated.


CONCLUSIONS
Our data suggest that TNFα is a critical cytokine that amplifies the response of the nephron to immune complex deposition, but that it has less influence on the response of the systemic vasculature to inflammation.
Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
Ramalingam
R
Bethunaickan
Ranjit
R
Sahu
Zheng
Z
Liu
Yi Ting
YT
Tang
Weiqing
W
Huang
Osarieman
O
Edegbe
Haiou
H
Tao
Meera
M
Ramanujam
Michael P
MP
Madaio
Anne
A
Davidson
D000818:Animals; D000936:Antigen-Antibody Complex / Q000187:drug effects* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D016898:Interferon-alpha; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008181:Lupus Nephritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha