Therapeutic studies in new zealand mice

Abstract

In view of the known inhibitory effects of androgens on the spontaneous production of autoantibodies in hybrids of NZB mice, as well as the dramatic effects of sex hormones on the modulation of autoimmunity in NZB/NZW F1 mice, we undertook a systematic study of treatment of female NZB/NZW mice with androgens. We initiated treatment at 0.5, 3, 5, 6, 7, or 8 months of life in castrated or intact mice by use of one of three steroid preparations at different doses. We found that danazol was not effective in suppressing proteinuria, reducing antibodies to ssDNA, or in prolonging survival. In contrast, both testosterone and 5 α‐dihydrotestosterone were capable of prolonging survival, suppressing proteinuria, and reducing anti‐ssDNA in both intact and castrated mice. Testosterone was effective at lower doses than was the 5 α hormone. Testosterone significantly prolonged survival even when started after the onset of clinical illness at 5, 7, and 8 months of age. Mice treated from 5 months of life with testosterone had a much more marked reduction in antibodies to ssDNA than to native DNA. However, treatment from 7 months of age significantly prolonged survival without altering the serum levels of either autoantibody, suggesting that some other mechanism of testosterone action may be contributing to therapeutic efficacy. These studies indicate that androgen therapy may be beneficial even after the development of clinical illness, that castration is not necessary for benefit, and that the effectiveness of a therapeutic regimen is dependent upon both the dose and the particular preparation of hormone.

Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

“…Estrogens have long been suspected of promoting systemic autoimmunity due to the striking female predominance, including a female-to-male ratio of 10:1 in human SLE and earlier disease onset in females in some murine lupus models, such as (NZBxNZW)F1 mice (Andrews et al 1978). Moreover, administration of exogenous estrogen has been shown to induce autoantibodies in non-autoimmune mice and accelerate disease in lupus-prone mice of both sexes, whereas ovariectomy or administration of testosterone to female lupus mice ameliorates disease (Apelgren et al 1996; Melez et al 1980; Roubinian et al 1978; Steinberg et al 1980; Verthelyi and Ahmed 1994; Verthelyi and Ahmed 1998). …”

Sex differences in autoimmune diseases

“…Oestrogen treatment is clearly protective in collagen induced arthritis (CIA) and pharmacologic blocking of both nuclear ERα and ERβ receptors abolished this protection [132-135]. In contrast, oophorectomy ameliorates murine lupus, while oestrogen treatment, even at physiologic doses, accelerates disease [136-138]. The mechanism for the deleterious effect of oestrogen on murine lupus appears to involve, at least in part, an oestrogen induced effect on genes involved in survival and apoptosis of B cells which results in a skewing of naïve B cells towards autoimmunity [139-142].…”

New Experimental Models of Diabetic Nephropathy in Mice Models of Type 2 Diabetes: Efforts to Replicate Human Nephropathy

“…Mice are also prone to autoimmune disease as the kidneys exhibit light microscopic features that resemble lupus nephritis, not just diabetes lesions. The changes include glomerular proliferation, mesangial deposits, mild basement membrane thickening, and glomerulosclerosis [31, 32]. Eosinophilic nodules may be seen in some glomeruli, with occasional hyalinization of the glomerular arterioles and healing arteriolar inflammation [31, 32].…”