EXTENDED REPORT

Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies

Z M Sthoeger¹, H Zinger², E Mozes²

¹ Department of Medicine B, Kaplan Medical Centre, Rehovot, Israel
² Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

Correspondence to:
Correspondence to:
Dr Z M Sthoeger, Department of Medicine B, Kaplan Medical Centre, Rehovot, Israel;
sthoeger{at}012.net.il

Background: Sex hormones have been shown to influence the immune system and to modify the course of autoimmune disorders.

Objective: To examine the effects of the oestrogen antagonist tamoxifen on the course of systemic lupus erythematosus (SLE) in (NZBxNZW)F1 mice.

Methods: Groups of 8 week old (NZBxNZW)F1 female mice were treated with tamoxifen (800 µg/mouse; twice a week) or with double distilled water for four months. Mice were evaluated monthly for the presence of autoantibodies directed against DNA and nuclear extract (NE) by enzyme linked immunosorbent assay (ELISA). White blood cells and thrombocytes were quantified by a cell counter and proteinuria by combistix kit. At 6 months of age, all mice that did not die spontaneously were killed and evaluated for the presence of glomerular immune deposits by indirect immunofluorescence assay. IgG isotypes of autoantibodies in the mouse sera and glomeruli were determined by chain specific antibodies.

Results: Tamoxifen treatment significantly reduced autoantibody production directed against either NE or DNA. The latter reduction was mainly in autoantibodies of the IgG3 isotype. Furthermore, tamoxifen had significant beneficial effects on the course of SLE in (NZBxNZW)F1 mice. At 6 months of age, 40% of the untreated mice died spontaneously, whereas all the tamoxifen treated mice were still alive. All untreated mice showed severe thrombocytopenia and persistent proteinuria, with diffuse glomerular immune deposits of IgG2a and IgG3 isotypes in their kidneys. In contrast, the tamoxifen treated mice had a normal number of thrombocytes and only minimal proteinuria. Moreover, glomerular immune deposits were detected in <40% of the tamoxifen treated mice. The latter were mainly of the IgG2a but not of the IgG3 isotype.

Conclusion: The results clearly show the remarkable therapeutic effects of tamoxifen on SLE of (NZBxNZW)F1 female mice and suggest that these beneficial effects are related to the specific reduction of IgG3 autoantibodies.

Keywords: systemic lupus erythematosus; anti-DNA isotypes; tamoxifen; sex hormone immunomodulation

Abbreviations: DDW, double distilled water; ds, double stranded; ELISA, enzyme linked immunosorbent assay; FITC, fluorescein isothiocyanate; Id, idiotype; IL, interleukin; NE, nuclear extract; SLE, systemic lupus erythematosus; ss, single stranded; TNF, tumour necrosis factor; WBC, white blood cells

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Pauklin, S., Petersen-Mahrt, S. K. (2009). Progesterone Inhibits Activation-Induced Deaminase by Binding to the Promoter. J. Immunol. 183: 1238-1244 [Abstract] [Full Text]  
• Ichii, O, Konno, A, Sasaki, N, Endoh, D, Hashimoto, Y, Kon, Y (2009). Onset of autoimmune glomerulonephritis derived from the telomeric region of MRL-chromosome 1 is associated with the male sex hormone in mice. Lupus 18: 491-500 [Abstract]  
• Ryan, M. J. (2009). Young Investigator Award Lecture of the APS Water and Electrolyte Homeostasis Section, 2008: The pathophysiology of hypertension in systemic lupus erythematosus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296: R1258-R1267 [Abstract] [Full Text]  
• Arias, C. F., Ballesteros-Tato, A., Garcia, M. I., Martin-Caballero, J., Flores, J. M., Martinez-A, C., Balomenos, D. (2007). p21CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses. J. Immunol. 178: 2296-2306 [Abstract] [Full Text]  
• Sereda, D., Werth, V. P. (2006). Improvement in Dermatomyositis Rash Associated With the Use of Antiestrogen Medication. Arch Dermatol 142: 70-72 [Abstract] [Full Text]  
• Nalbandian, G., Paharkova-Vatchkova, V., Mao, A., Nale, S., Kovats, S. (2005). The Selective Estrogen Receptor Modulators, Tamoxifen and Raloxifene, Impair Dendritic Cell Differentiation and Activation. J. Immunol. 175: 2666-2675 [Abstract] [Full Text]  
• Peeva, E., Venkatesh, J., Diamond, B. (2005). Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival. J. Immunol. 175: 1415-1423 [Abstract] [Full Text]  
• Koller, M D, Templ, E, Riedl, M, Clodi, M, Wagner, O, Smolen, J S, Luger, A (2004). Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus. Ann Rheum Dis 63: 1677-1680 [Abstract] [Full Text]