Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice.
OBJECTIVE
While estrogen treatment exacerbates disease in models of systemic lupus erythematosus (SLE), the effects of progesterone are unclear. This study was undertaken to assess the effects of continuous progesterone treatment on autoantibody production and spontaneous glomerulonephritis (GN) in a mouse model of SLE.


METHODS
Female (NZBxNZW)F1 (NZB/NZW) mice were treated with vehicle, 2 mg of depot medroxyprogesterone acetate (DMPA), or 10 mg of DMPA every 6 weeks. Survival, proteinuria, and serum anti-double-stranded DNA (anti-dsDNA) levels were monitored. At 39 weeks of age, kidneys were analyzed for abnormalities and glomerular accumulation of IgG subclasses and C3. Spleen leukocyte subsets were also analyzed.


RESULTS
DMPA treatment reduced mortality in a dose-dependent manner in association with reduced proteinuria and glomerular damage. High-dose DMPA treatment resulted in a reduction of total serum IgG and IgG2a anti-dsDNA antibody levels, whereas IgG1 anti-dsDNA antibody levels were modestly increased. High-dose DMPA reduced glomerular accumulation of IgG1, IgG2a, IgG3, and complement, while low-dose DMPA decreased glomerular IgG2a and IgG3 levels compared with vehicle treatment.


CONCLUSIONS
Our findings indicate that treatment of premorbid female NZB/NZW mice with DMPA reduces mortality and attenuates spontaneous GN, likely through multiple mechanisms, including altered ratios of protective Th2-related IgG antibodies versus nephritogenic Th1-related IgG autoantibodies. Thus, estrogen and progesterone may have disparate effects on lupus autoimmunity, lending new significance to observed hormonal imbalances in patients with SLE. These data also suggest that treatment of SLE patients with DMPA may have therapeutic benefit.
Hughes
Grant C
GC
Department of Medicine, University of Washington, Seattle, WA 98195, USA. hughesg@u.washington.edu
Martin
David
D
Zhang
Kang
K
Hudkins
Kelly L
KL
Alpers
Charles E
CE
Clark
Edward A
EA
Elkon
Keith B
KB
D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism; D003176:Complement C3 / Q000378:metabolism; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology*; D007074:Immunoglobulin G / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology* / Q000473:pathology; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D051379:Mice; D008814:Mice, Inbred NZB; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
D001323:Autoantibodies; D051940:B7-2 Antigen; D003176:Complement C3; D007074:Immunoglobulin G; D011374:Progesterone; D004247:DNA; D017258:Medroxyprogesterone Acetate