FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice.
FTY720 is a novel investigational agent targeting the sphingosine 1-phosphate (S1P) receptors with an ability to cause immunosuppression by inducing lymphocyte sequestration in lymphoid organs. Systemic lupus erythematosus (SLE) is refractory autoimmune disease characterized by the production of a wide variety of autoantibodies and immune complex (IC)-mediated lupus nephritis. Among several SLE-prone strains of mice, BXSB is unique in terms of the disease-associated monocytosis in periphery and the reduced frequency of marginal zone B (MZ B) cells in spleen. In the present study, we examined the effect of FTY720 on lupus nephritis of BXSB mice. FTY720 treatment resulted in a marked decrease in lymphocytes, but not monocytes, in peripheral blood, and caused relocalization of marginal zone B (MZ B) cells into the follicle in the spleen. These changes did not affect the production of autoantibodies, thus IgG and C3 were deposited in glomeruli in FTY720-treated mice. Despite these IC depositions, FTY720-treated mice showed survival advantage with the improved proteinuria. Histological analysis revealed that FTY720 suppressed mesangial cell proliferation and inflammatory cell infiltration. These results suggest that FTY720 ameliorates lupus nephritis by inhibiting the end-stage inflammatory process following IC deposition in glomeruli.
Department of Rheumatology and Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. andosei78102@biscuit.ocn.ne.jp
Seiichiro
S
Ando
Hirofumi
H
Amano
Eri
E
Amano
Kentaro
K
Minowa
Takashi
T
Watanabe
Soichiro
S
Nakano
Yutaka
Y
Nakiri
Shinji
S
Morimoto
Yoshiaki
Y
Tokano
Qingshun
Q
Lin
Rong
R
Hou
Mareki
M
Ohtsuji
Hiromichi
H
Tsurui
Sachiko
S
Hirose
Yoshinari
Y
Takasaki
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007958:Leukocyte Count; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D008181:Lupus Nephritis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D050527:Mesangial Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013154:Spleen / Q000187:drug effects / Q000276:immunology
D000974:Antibodies, Antinuclear; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine