Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Long-Term Anti-CD20 Treatment Reduces Antibody-Secreting Ells in NZB/W Lupus Mouse.

Wang2,  Wensheng, Owen2,  Terasa, Ichikawa2,  Travis, Anolik1,  Jennifer H.

University of Rochester, Rochester, NY
University of Rochester Medical Center, Rochester, NY

Objective:

Although anti-CD20 antibody efficiently depletes most B cells, B-cell depletion (BCD) has shown variable efficacy in clinical trials as a therapy for systemic lupus erythematosus (SLE). To better understand the mechanisms of action of anti-CD20 and the effect on SLE, a lupus-prone mouse model was used to study the alteration in antibody-secreting cells after B cell depletion.

Methods:

For short-term treatment, NZB/NZWF1 female mice (24–30 wks old) with durable proteinuria > 2+ (100 mg/dl) were dosed weekly × 4 with anti-mCD20 antibody (IgG2a, a gift from Biogen Idec)(n=6) or control antibody IgG2a and sacrificed 1 wk after the last treatment. To study longer-term effects of BCD, 27 wk old NZB/NZWF1 female mice with high titer anti-dsDNA antibodies were dosed weekly with anti-mCD20 antibody or control IgG via retro-orbital injection. One group was treated weekly × 4 (n= 6) and sacrificed 8 wks later. Another was treated weekly × 12 (n= 6) and sacrificed 1 wk after the last treatment. Cells from spleen, bone marrow (BM) and kidney were collected and total IgG and dsDNA antibody secreting cells (ASC) were determined by ELIspot.

Results:

Nephritis improved after anti-mCD20 treatment (neither 4 wks nor 12 wks treated mice were found to develop nephritis [3+ proteinuria]) compared to control (5/6 mice developed nephritis 4+). Although BCD was efficient (>90% B220+ cell depletion), there was no difference in the numbers of anti-dsDNA-secreting cells and total IgG-secreting cells in either spleen, BM or kidney after 4 treatments of anti-mCD20, over the short-term (evaluation 1 wk after the last treatment- see Table) or long-term (evaluation 8 wks after the last treatment, data not shown). Interestingly, in untreated mice the ratio of anti-dsDNA/total IgG-secreting cells in the kidney was significantly higher than in spleen and BM (p<10-4) suggesting that the kidney is a reservoir of either production or maintenance of autoreactive ASCs. In striking contrast, long-term treatment with anti-mCD20 resulted in significant decreases in total IgG and anti-dsDNA-secreting cells in spleen. In addition, the average size of total IgG-secreting cell spots from kidney decreased significantly, suggesting a shift in the antibody producing capacity after anti-mCD20.

Conclusion:

Long-term anti-CD20 treatment significantly reduces ASCs in spleen and moderately reduces ASCs in bone marrow and kidney. Treatment also appears to alter antibody secretion in kidney. Therefore, longer term B cell depletion may have increased efficacy as a treatment for SLE.

 Short-term Treatment
 IgGdsDNA
 Ctrla-CD20t-testCtrla-CD20t-test
Spleen115.6 ± 35.661.9 ± 17.50.123.4 ± 1.02.6 ± 0.580.3
BM15.9 ± 4.221.2 ± 3.20.260.66 ± 0.170.46 ± 0.110.28
Kidney68.3 ± 4.181.5 ± 21.00.1130.3 ± 8.837.3 ± 8.30.18
 Long-term Treatment
 IgGdsDNA
 Ctrla-CD20t-testCtrla-CD20t-test
Spleen132.2 ± 23.04.21 ± 3.660.00112.03 ± 0.300.21 ± 0.150.00091
BM33.27 ± 7.0212.9 ± 4.540.0320.80 ± 0.220.18 ± 0.060.018
Kidney269.8 ± 64.9385.86 ± 19.850.02863.77 ± 17.773.58 ± 1.760.013
per 10E4 cells

To cite this abstract, please use the following information:
Wang, Wensheng, Owen, Terasa, Ichikawa, Travis, Anolik, Jennifer H.; Long-Term Anti-CD20 Treatment Reduces Antibody-Secreting Ells in NZB/W Lupus Mouse. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :436
DOI: 10.1002/art.28205

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