- Paper Report
- Open Access
zTNF4 blockade in murine lupus
- Chaim Putterman1
© Current Science Ltd 2000
- Published: 18 July 2000
- systemic lupus erythematosus
- TNF receptor family
In a recent paper report, I discussed an article describing mice overexpressing BAFF (also known as zTNF4, BLyS, TALL-1, and THANK), a newly described member of the TNF family. BAFF transgenic mice displayed a significant expansion of the B cell compartment, due to increased proliferation and/or prolonged B cell survival. Furthermore, lupus-like autoimmune features were found in BAFF-transgenic mice. Interfering with the interaction between BAFF and its ligand could be of great value in the treatment of autoimmune disease. To confirm a role for BAFF in lupus, identify its receptor(s), and examine if blocking BAFF-BAFF receptor interactions is effective in the treatment of murine SLE.
The zTNF4-transgenic mice were generally similar to the previously described BAFF-transgenic mice. FACS analysis showed a significant increase in the number as well as proportion of B220+ B cells in the spleen and lymph nodes in transgenic mice as compared to controls. In contrast to BAFF-transgenic mice, the zTNF4-transgenics contained large numbers of B-1a cells in the spleen. While the number of splenic T cells was unchanged, CD4+ and CD8+ T cells were in an activated state. Serum IgM and IgG were increased several fold in the majority of transgenic mice. Older zTNF4-transgenic mice developed anti-double-stranded (ds) DNA antibodies, several at high titer. In addition, proteinuria and glomerulonephritis were found. Serum zTNF4 levels increased with age in the lupus-prone MRL-lpr/lpr and B/W mouse models, and were highest in the most severely affected mice. Two orphan TNF receptor family molecules, TACI and BCMA, were idenified as receptors for zTNF4. TACI-Ig prevented the binding of zTNF4 to human B cells, as well as its stimulatory effects on murine and human B cells in vitro. Administration of TACI-Ig to B/W mice from 21 to 26 weeks of age delayed the onset of severe proteinuria for up to 10 weeks after treatment was stopped. Importantly, survival increased to 100% at 38 weeks in treated mice compared with only 47% in controls; however, there were no differences in anti-dsDNA antibody titers. After TACI-Ig treatment, the percentages of peripheral blood B cells was significantly decreased (by 53% at the high treatment dose) at week 28, but returned to control levels by week 37.
Mice overexpressing zTNF4 under the control of a lymphoid-specific promoter were generated and analyzed for changes in B cells and T cells, as well as for renal disease. Transgene expression was verified by PCR and high levels of zTNF4 by ELISA. Genes for zTNF4 receptors were identified by staining COS7 cells, transfected with a cDNA library from a B cell line, with labeled zTNF4 (receptor cloning). A soluble version of one receptor was created by fusing the extracellular domain of TACI to the Fc portion of human IgG1 (TACI-Ig), and was administered to lupus-prone NZB x NZW F1 (B/W) mice.
- Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH: TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000, 404: 995-999.PubMedView ArticleGoogle Scholar