Function of the Th17/interleukin-17A immune response in murine lupus nephritis.
OBJECTIVE
The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin-17 (IL-17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL-17A immune response in 2 murine models of lupus nephritis.


METHODS
IL-17A-deficient MRL/MPJ-Fas(lpr) /2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus-prone (NZB × NZW)F1 (NZB/NZW) mice were treated with anti-IL-17A and anti-interferon-γ (anti-IFNγ) antibodies, and their effects on the clinical course of lupus nephritis were assessed.


RESULTS
Characterization of renal IL-17A-producing and IFNγ-producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL-17A+ cells. Renal IL-17A was mainly produced by CD4/CD8 double-negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL-17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL-17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti-IFNγ treatment attenuated the severity of the disease.


CONCLUSIONS
The Th17/IL-17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL-17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.
Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
Tilman
T
Schmidt
Hans-Joachim
HJ
Paust
Christian F
CF
Krebs
Jan-Eric
JE
Turner
Anna
A
Kaffke
Sabrina B
SB
Bennstein
Tobias
T
Koyro
Anett
A
Peters
Joachim
J
Velden
Stefanie
S
Hünemörder
Friedrich
F
Haag
Oliver M
OM
Steinmetz
Hans-Willi
HW
Mittrücker
Rolf A K
RA
Stahl
Ulf
U
Panzer
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007111:Immunity, Cellular / Q000276:immunology / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000473:pathology / Q000502:physiology; D058504:Th17 Cells / Q000473:pathology / Q000502:physiology*
D000888:Antibodies, Anti-Idiotypic; D017252:CD3 Complex; D020381:Interleukin-17; D007371:Interferon-gamma