Effects of FTY720 in MRL-lpr/lpr mice: therapeutic potential in systemic lupus erythematosus.
OBJECTIVE To examine the effects of a novel immunosuppressant, FTY720, on hematolymphoid cells and the clinical course of MRL-lpr/lpr (MRL/lpr) mice genetically predisposed to systemic lupus erythematosus (SLE).


METHODS
Apoptosis of hematolymphoid cells was determined in vitro by FACScan after staining with propidium iodide or merocyanine 540. From 4 months of age, 15 female MRL/lpr mice received oral administration of 2 mg/kg each of FTY720, methylprednisolone (mPSL), or vehicle, 3 times per week. Therapeutic efficacy was evaluated by levels of anti-dsDNA antibodies in serum and the survival rate. In parallel, T cell proliferation and secretion of interleukin 2 (IL-2) induced by anti-CD3, phenotypes of the spleen, lymph node and bone marrow cells, as well as immunohistochemistry of the kidney, were examined in vitro.


RESULTS
FTY720 at 2 microM induced apoptosis in more than 70% of double negative (CD4-/CD8-) T cells from the spleen of MRL/lpr mice in vitro. Oral FTY720 was tolerated well with no apparent side effects. FTY720 treated and control mice gained weight at an identical pace through to 9 months of age. FTY720 significantly suppressed the production of anti-dsDNA antibodies (FTY720 vs control: 1739 +/- 898 U/ml vs 410 +/- 356 U/ml at 8 months of age; p < 0.05) and reduced the deposition of IgG in glomeruli compared to control animals. At 9 months of age, the survival rate in the FTY720 treated mice was 86.9% compared to 33.0% in controls (p < 0.01). FTY720 decreased the number of double negative T cells from the spleen and lymph nodes in vivo, and increased T cell proliferation and IL-2 secretion induced by anti-CD3 stimulation in vitro.


CONCLUSIONS
FTY720 suppressed the development of autoimmunity and prolonged the lifespan of female MRL/lpr mice. Suppression of autoimmunity, at least in part, may have resulted from an apoptogenic potential of FTY720. Hence, it could be useful for primary or adjunctive therapy of human SLE.
Okazaki
Hitoaki
H
Department of Medicine, Jichi Medical School, Tochigi, Japan.
Hirata
Daisuke
D
Kamimura
Takeshi
T
Sato
Hidetomo
H
Iwamoto
Masahiro
M
Yoshio
Taku
T
Masuyama
Junichi
J
Fujimura
Akio
A
Kobayashi
Eiji
E
Kano
Shogo
S
Minota
Seiji
S
D000284:Administration, Oral; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000936:Antigen-Antibody Complex / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry / Q000379:methods; D007074:Immunoglobulin G / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008775:Methylprednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D004247:DNA; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D008775:Methylprednisolone