Modulation of autoantibody production by mycophenolate mofetil: effects on the development of SLE in (NZB x NZW)F1 mice.
BACKGROUND
Mycophenolate mofetil (MMF) has been successfully used to improve or prevent the development of systemic lupus erythematosus (SLE) in both humans and in several lupus-prone mice. In the present study, we evaluated mechanisms through which MMF may exert its therapeutic effect on the development of systemic autoimmunity.


METHODS
(NZBxNZW)F(1) female mice were continuously treated with 100 mg/kg/day (high dose) or 30 mg/kg/day (low dose) MMF beginning at 3 months of age. The development of an autoimmune syndrome was evaluated by measuring immunoglobulin (Ig) isotypes of autoantibodies and their levels, as well as by evaluating immunopathological kidney abnormalities and mortality curves.


RESULTS
At both doses, MMF efficiently modulated the development of SLE. Although the higher dose of MMF directly inhibited the production of autoantibodies, 30 mg/kg/day MMF promoted qualitative but not quantitative changes in autoantibodies in (NZB x NZW)F(1) female mice. These qualitative changes were manifested as a selective reduction in total or antigen-specific IgG2a antibody levels.


CONCLUSIONS
The mechanisms through which MMF controls the development of SLE in (NZB x NZW)F(1) females is highly dependent upon immunosuppressor dose. Interestingly, lower dose MMF selectively reduced IgG2a antibody levels, suggesting that this dose may modulate T(H1) CD4+ activity.
Ramos
Maria Angeles
MA
Servicio de Nefrología, Unidad de Investigación, Hospital Universitario Marqués de Valdecilla, Av. Valdecilla s/n, E-39008 Santander, Spain.
Piñera
Celestino
C
Setién
Maria Angeles
MA
Buelta
Luis
L
de Cos
Maria Angeles
MA
de Francisco
Angel-Luis M
AL
Merino
Ramón
R
Arias
Manuel
M
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001323:Autoantibodies; D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid