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. Genetic, viral, and hormonal factors are involved in a pathogenetic mechanism that is manifest primarily as a disturbance in immunologic regulation. Recent studies on the sequential development of IgM and then IgC antibodies to DNA and RNA suggest that the thymus, spleen, and gonads exert important regulatory influences. We have found that sex hormones modulate the expression of autoimmunity in B/W mice, with androgens suppressing and estrogens accelerating disease. The hormones may act by restoring immunologic control.Animal models for human illness provide an unusual opportunity to study preclinical disease that is only rarely possible in human medicine. Such studies can lead to valuable insights into pathogenetic mechanisms underlying early events in disease and offer the hope of finding more specific and effective modes of prophylaxis or therapy.There are now several animal models for human lupus, including a new mouse strain called MRL, and a
. Genetic, viral, and hormonal factors are involved in a pathogenetic mechanism that is manifest primarily as a disturbance in immunologic regulation. Recent studies on the sequential development of IgM and then IgC antibodies to DNA and RNA suggest that the thymus, spleen, and gonads exert important regulatory influences. We have found that sex hormones modulate the expression of autoimmunity in B/W mice, with androgens suppressing and estrogens accelerating disease. The hormones may act by restoring immunologic control.Animal models for human illness provide an unusual opportunity to study preclinical disease that is only rarely possible in human medicine. Such studies can lead to valuable insights into pathogenetic mechanisms underlying early events in disease and offer the hope of finding more specific and effective modes of prophylaxis or therapy.There are now several animal models for human lupus, including a new mouse strain called MRL, and a
In these studies we investigated the modifying effect of sex hormones on both the levels of induced antibodies after immunization with single-stranded DNA (ssDNA) and the levels of spontaneously produced anti-T cell antibodies (NTA). To learn whether the responses were genetically determined or under hormonal regulation, we analyzed hybrids produced by crossing the autoimmune NZB strain with the nonautoimmune DBA/2 strain. For both anti-ssDNA and NTA, males usually had a lower response than females; this difference could largely be removed by castration of the males. Females given testosterone implants also had decreased antibody levels. The higher responses in females and suppression by testosterone were true for all mice studied except NZB mice. NZB mice appear to have an insensitivity to the suppressive effects of testosterone. NZB mice spontaneously produce a variety of autoantibodies and serve as a model of autoimmunity, particularly systemic lupus erythematosus (SLE) (1). As they age, NZB mice produce antibodies to erythrocytes, thymocytes, T cells, and nucleic acids, especially singlestranded DNA (ssDNA) (2). Because both antibodies against T cells (NTA) and antinucleic acid antibodies are characteristic of NZB mice and may be important in the pathogenesis of autoimmunity, it is critical to investigate the mode of inheritance of the propensity for development of these autoantibodies.Because of the known preponderance of SLE in females (3,4), we studied the effects of sex hormones on the production of anti-T cell antibodies and antissDNA antibodies. An increasing body of evidence suggests that sex hormones influence both spontaneous autoantibody production (5-7) and antibody response to immunization (8). Sex hormones can affect immune responses, but generalizations are difficult to establish due to the variety of experimental systems and pharmacologic doses of hormones frequently employed. There is abundant evidence for enhanced immunologic responses in females over that of males; however, the underlying mechanisms to account for these differences are as yet unknown.Genetic factors have been implicated in the development of autoimmunity in New Zealand mice (9-19). In addition, X-linked immune response genes have been described for synthetic (20) and naturally occurring nucleic acids (21). In the studies discussed here, we investigated the modifying effect of sex hormones on both the levels of induced antibodies after immunization with single-stranded DNA and the levels of spontaneously produced anti-T cell antibodies. In order to determine if these responses were genetically determined or under hormonal regulation, we analyzed hybrids produced by crossing the autoimmune NZB strain with the nonautoimmune DBA/2 strain. The DBAP strain was chosen as one of the parental strains because: 1) it is H-2* like NZB mice (22), 2) like NZB mice it expresses gp70 viral protein antigens in large quantities on the surface of mononuclear cells (23), 3) DBA/2 mice do not spontaneously produce large quantities of either NTA...
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.
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