Effect of 5-  Dihydrotestosterone on T-cell Proliferation of the Female Nonobese Diabetic Mouse

Abstract

Nonobese diabetic (NOD) mice develop type I diabetes spontaneously and have been utilized as a model for human autoimmune insulin-dependent diabetes. The disease is caused by the destruction of insulin-producing beta cells in the pancreatic islet of Langerhans by infiltrating inflammatory cells, which are primarily T lymphocytes. The incidence of diabetes in NOD mice is increased in females compared with males, suggesting that sex steroid hormones play an important role in the development of the disease. We therefore investigated the effect of a male steroid, 5-alpha-dihydrotestosterone (5DHT), on disease development, T-cell phenotype, T-cell proliferation, and cytokine profiles in this model. None of the mice that received 5DHT for 120 days (n = 7) developed insulitis, whereas all control mice (n = 8) developed the disease. The percentage of CD4+ T cells in peripheral blood mononuclear cells was markedly decreased in the 5DHT-treated females compared with those in controls (37.1 +/- 4.8 vs 51.3 +/- 9.3, P < 0.02), whereas no significant differences in the percentage of CD8+ T cells were observed between treated and control female mice. Results of a syngeneic mixed lymphocyte reaction (SMLR) also suggested that T cells are major target cells of 5DHT administration. An increased expression of IL-4 mRNA, representing T helper 2 (Th2) T cells, was observed in the SMLR. On the basis of these results, a systemic administration of 5DHT appears to have direct effects on the expansion of Th2 cell populations with subsequent restoration of normal immune responses.

Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease

“…Castration or administration of sex hormones can regulate disease incidence (72), suggesting an interaction of sex hormones and immune function (73). In our study, transgenic GAD65 expression induced a disease incidence of approximately 70% in line 14 males, comparable to that in non-tg(ϩ) NOD females.…”

Contribution of T cells to the development of autoimmune diabetes in the NOD mouse model

“…(59) A recent study demonstrated that 5-DHT administration to female NOD mice may promote Th2 cell development, which in turn prevent the development of insulitis, as well as diabetes. (58) More recently, a similar finding was observed in an experimental autoimmune encephalomyelitis, an animal model for human multiple sclerosis. (60) It should be noted that a recent genetic study in human diabetes demonstrated that the evidence for linkage to a diabetogenic gene IDDM13, located on distal chromosome 2q, increased in families with excess affected females, and was reduced in those with affected males.…”

“…Evidence that male steroids may play a role in preventing the onset of type 1 diabetes is provided by studies, demonstrating that orchidectomy increases the disease development (50)(51)(52)(53) and 5␣-dihydrotestosterone (5-DHT) is able to prevent the disease development, (50)(51)(52)(53)(54)(55)(56)(57)(58) but not the insulitis in sexually matured NOD females. (56) Interestingly, estrogen administration to lymphoid cells upregulates IFN-␥ promoter activity.…”

“…A recent study conducted by our group may suggest that immunomodulation by a male steroid at this stage is effective to prevent the onset of peri-insulitis. (58) This review does not discuss the roles of non-T cells, such as macrophages, in the development of diabetes. For example, IL-12 secreted mostly by macrophages plays a critical role in the Th1 cell functions.…”

Dehydroepiandrosterone sulfate does not prevent spontaneous and iodine-induced lymphocytic thyroiditis and diabetes mellitus in the BB/Wor rat

“…Ovariectomy increases the incidence and severity of DM and a replacement dose of estrogen given for two weeks prevents increases in blood glucose and circulating insulin levels (49). Furthermore, 5a-dihydrotestosterone (5aDHT) administration to the NOD mouse prevented the development of insulitis (51). However, spontaneous DM in the C57BL/KsJ mouse does not have a gender-specific preference, yet DHEA administration markedly decreased the occurrence of DM (9).…”