Immunomodulatory Function of Vitamin D and Its Role in Autoimmune Thyroid Disease.

Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.

Prunella vulgaris L. attenuates experimental autoimmune thyroiditis by inducing indoleamine 2,3-dioxygenase 1 expression and regulatory T cell expansion.

BACKGROUND: Prunella vulgaris L. (P. vulgaris) has traditionally been used to treat swelling and inflammation of the thyroid gland. This study aimed to evaluate the effects of P. vulgaris on experimental autoimmune thyroiditis (EAT) and explore the roles of indoleamine 2,3-dioxygenase 1 (IDO1) and regulatory T cells (Tregs) in these P. vulgaris-mediated effects. METHODS: The main bioactive compounds in P. vulgaris were analysed by high-performance liquid chromatography. An EAT model was established by immunization of Lewis rats with thyroglobulin via subcutaneous injection. Thyroid volume was assessed by ultrasound, and lymphatic infiltration in the thyroid was evaluated by haematoxylin and eosin staining. The serum levels of thyroglobulin antibody (TgAb) and cytokines were measured by indirect enzyme-linked immunosorbent assay. The percentage of CD4+CD25+Foxp3+ Tregs was detected by flow cytometry. The mRNA and protein levels of IDO1 were measured by qRT-PCR and Western blotting, respectively. The levels of tryptophan (Trp) and kynurenine (Kyn) in serum and faecal samples were assessed with a fluorometric kit and spectrophotometry. RESULTS: The main bioactive compound in P. vulgaris was rosmarinic acid. The TgAb level and thyroid volume in EAT rats were significantly decreased after administration of P. vulgaris (P < 0.01). The inflammation score in EAT rats that were administered P. vulgaris was significantly lower than that in the EAT controls (P < 0.01). In addition, P. vulgaris promoted the expansion of splenic Tregs and increased the production of IL-10 and TGF-ß (P < 0.01) in EAT rats. Moreover, P. vulgaris induced IDO1 mRNA and protein expression in the spleen and intestine in P. vulgaris-treated EAT rats (P < 0.01). Finally, Trp levels were reduced and Kyn levels and the Kyn/Trp ratio were increased in the serum of P. vulgaris-treated EAT rats. CONCLUSION: We were the first to demonstrate the role of IDO1-induced Treg expansion in P. vulgaris-mediated attenuation of EAT. Our study provides insight into the immunopathogenesis of autoimmune thyroiditis and shows the potential therapeutic value of P. vulgaris.

Autoimmune thyroid diseases after 25 years of universal salt iodisation: an epidemiological study of Chinese adults in areas with different water iodine levels.

The present study aimed to evaluate the status of iodine nutrition and thyroid function in adults, to understand the distribution of thyroid disease in people with autoimmune thyroid disease (AITD) in different water iodine areas and to explore the relationship between serum iodine, urine iodine and thyroid function in people with AITD. A cross-sectional survey was conducted in areas of Shandong Province with different water iodine levels, and subsequently 1225 adults were enrolled from iodine-deficient (ID), iodine-adequate (IA) and iodine-excess (IE) areas. Urinary iodine, water iodine, salt iodine, serum iodine and thyroid function were measured. According to the urine iodine concentration, the ID and IA areas were defined as iodine sufficient and the IE area as iodine excessive. Urine iodine, serum iodine, free thyroxine (FT4) and thyroid-stimulating hormone (TSH) levels were comparatively higher in the IE area. The positive rate of thyroglobulin antibody (19·1 %) and the prevalence of AITD (21·8 %) were higher in the ID areas; the prevalence of subclinical hypothyroidism was lowest in the ID areas (7·3 %) and highest in the IE area (16·3 %). Among the AITD population, urinary iodine concentration, free triiodothyronine, FT4 and TSH had a non-linear correlation with serum iodine; abnormal TSH level, serum iodine concentration > 110 µg/l and goitre were risk factors for AITD in adults, especially females. Our data collectively suggest that universal salt iodisation has improved the iodine nutritional status of the population in ID areas in China. Non-step-by-step iodine fortification may induce the transformation of thyroid autoimmune diseases from recessive-to-dominant in susceptible people. Moreover, enhanced monitoring of thyroid function in people with AITD is important.

Endocrine disruptors and thyroid autoimmunity.

Many papers evaluated the effect of the environmental, or occupational endocrine disruptors (ED), on the thyroid gland, that can lead to thyroid autoimmunity. A higher prevalence of autoimmune thyroid diseases (AITD) was observed in people living in polluted areas near to petrochemical plants, and in petrochemical workers, but also in area contaminated with organochlorine pesticides, or with polychlorinated biphenyls, or near aluminum foundries. The exposure to Hg in chloralkali workers, or in swordfish consumers has been also found to increase AITD prevalence. Vanadium has been shown to increase the inflammatory response of thyrocytes. A beneficial effect of omega-3 fatty acids, and of myo-inositol and selenomethionine have been shown to counteract the appearance of AITD in subjects exposed to environmental or occupational ED. More large studies are needed to investigate the potential roles of ED in the induction of AITD, and of agents or habits that are able to prevent them.

Stable consumption of swordfish favors, whereas stable consumption of oily fish protects from, development of postpartum thyroiditis.

PURPOSE: In 236 pregnant women, we showed that selective or predominant consumption of swordfish (group A) was associated with high rates of positivity for serum thyroid autoantibodies (TPOAb and TgAb) throughout day 4 postpartum. In contrast, selective or predominant consumption of oily fish (group B) was associated with TPOAb and TgAb negativity. Rates were intermediate in group C (scanty consumption of swordfish) and group D (consumption of fish other than swordfish and oily fish). Gestational TPOAb positivity is a risk factor for postpartum thyroiditis (PPT), which evolves into permanent hypothyroidism (PH) in about 50% of cases. Purpose of this study was to verify that the different rates of thyroid autoantibodies in the four groups translated into different PPT rates. METHODS: We expanded our previous cohort (n = 412) and duration of follow-up (month 12 postpartum), and measured frequency of PPT and PH. RESULTS: At first timester of gestation, we confirmed the different Ab positivity rates in group A vs. group B (TPOAb = 21.7% vs. 4.7%, P < 0.0001; TgAb = 14.1% vs. 2.4%, P < 0.05). Overall, PPT prevalence was 63/412 (15.3%), but 22/92 in group A (23.9%), 4/85 in group B (4.7%; P < 0.0001 vs. group A), 17/108 (15.7%) in group C, and 16/117 (13.7%) in group D. Approximately half of the PPT women had PH, regardless of fish group. CONCLUSIONS: In conclusion, stable consumption of oily fish (which is enriched in polyunsaturated omega-3 fatty acids) protects from PPT, while stable consumption of swordfish (which is enriched in pollutants) favors PPT. Thus, a dietary prophylaxis of PPT is possible.

Effects of selenium and vitamin C on the serum level of antithyroid peroxidase antibody in patients with autoimmune thyroiditis.

PURPOSE: Selenium (Se), an essential trace element, has been implicated in pathogenesis of autoimmune thyroiditis (AIT). Most studies attributed the immune modulating effects of Se to its antioxidant properties. However, there is insufficient evidence to support the use of selenium supplementation or other antioxidants in patients with AIT. This clinical trial was designed to investigate the impact of Se and vitamin C supplementation on antithyroid peroxidase antibody (TPO-Ab) level in patients with AIT. METHODS: One hundred and two subjects aged 15-78 years were randomized into three groups. Group one (GI) (n = 38) was treated with 200 µg/day sodium selenite, group two (GII) (n = 36) received 500 mg vitamin C/day, and group three (GIII) (n = 28) received placebo over a 3-month period. Thyroid stimulating hormone (TSH), TPO-Ab, antithyroglobulin antibody (Tg-Ab) and Se concentrations were once measured before treatment and at the end of the study. RESULTS: After 3 months, TPO-Ab concentrations decreased within Se and vitamin C-treated groups, but did not change in the placebo subjects. In this regard, there was no significant difference between the groups. We also did not find any statistically significant difference in TSH and Tg-Ab levels within and between the groups. At the end of the study, Se level was significantly higher in GI compared with GII and GIII. CONCLUSION: Our findings supported the hypothesis of antioxidant beneficial effects of Se in AIT. However, it was not superior to vitamin C, regarding its effects on thyroid-specific antibodies.

Autoimmune Thyroid Disease in Islet Transplant Recipients Discontinuing Immunosuppression Late After Lymphodepletion.

CONTEXT: Clinical islet transplantation (CIT) is an innovative strategy to treat highly selected individuals with type 1 diabetes mellitus (T1DM). Lymphodepletion with alemtuzumab or thymoglobulin is often used for induction therapy in CIT. Alemtuzumab was recently licensed as a treatment of relapsing remitting multiple sclerosis (RRMS). In RRMS, autoimmune thyroid disease (AITD) has developed in up to 40% of individuals treated with alemtuzumab. The appearance of AITD after CIT is not well described. We herein explore factors associated with AITD developing after CIT and any relationship with exposure to lymphodepleting antibodies (alemtuzumab or thymoglobulin). CASE DESCRIPTION: Five cases of AITD developing after CIT for T1DM are described. All were female. Four cases had received alemtuzumab (20 to 40 mg) prior to at least one islet infusion, and one received thymoglobulin induction. The presentation with AITD was 18 to 135 months after first transplant and 11 to 18 months after withdrawal of all maintenance immunosuppression (IS). Four cases presented with clinical and biochemical evidence of hyperthyroidism from Graves disease. One case presented with biochemical evidence of hypothyroidism and positive TSH receptor antibodies. All were treated with conventional therapies for AITD. CONCLUSIONS: Despite routine use of alemtuzumab, clinical presentations of AITD seem to be uncommon in patients with CIT receiving IS. However, AITD can develop after withdrawal of IS, highlighting the need for careful thyroid surveillance in this population.

Thyroid antibodies in euthyroid and subclinical hypothyroidic pregnant women with autoimmune hypothyroidism: effects on hematological parameters and postpartum hemorrhage.

OBJECTIVES: The aim of the study was to investigate the relationship between thyroid antibodies and hematological parameters in euthyroid or subclinical hypothyroidic (S H) pregnant women with autoimmune hypothyroidism and to verity whether these pregnant women are affected by a higher rate of postpartum hemorrhage. MATERIAL AND METHODS: Thirty-six out hyroid and 21 S H pregnant women with autoimmune thyroid disease and 52 healthy pregnant women were evaluated. The relationship between thyroid hormones, thyroid antibodies level, the dosage of Levotroxin (LT4) and hematological parameters and the amount of postpartum bleeding was investigated. RESULTS: The mean platelet volume (MPV), was significantly higher in the SH group than in the euthyroid group and in the euthyroid group than healthy group (p<0.001). Hemoglobin (Hb) was significantly lower in both the SH group and the euthyroid group than control group (p<0.001). Other hematological parameters and the amount of postpartum bleeding did not differ between the groups. The correlation between Hb and fT3, FT4 was significant and positive, whereas between Hb and T SH was significant and negative (r=0.3 p<0.01, r=0.2 p=0.01, and r = -0.18 p=0.04, respectively). There was a significant and negative correlation between the PLT count and FT4, PT and FT3 (r = -0.2 p=0.01, r = -0.3 p<0.01, and r = -0.3 p<0.01, respectively). CONCLUSION: It has been described that being thyroid antibody-positive (TAb+) may be a risk factor for anemia and high MPV. However euthyroid and SH pregnant women with thyroid antibodies do not differ in terms of other coagulation parameters and postpartum hemorrhage from healthy controls.

Low Population Selenium Status Is Associated With Increased Prevalence of Thyroid Disease.

CONTEXT: Epidemiological studies have supported the premise that an adequate selenium intake is essential for thyroid gland function. OBJECTIVE: The objective was to investigate whether the prevalence of thyroid disease differed in two areas that were similar, except for very different soil/crop selenium concentrations. DESIGN: Cross-sectional observational study. SETTING: The setting was two counties of Shaanxi Province, China, here defined as adequate- and low-selenium. PARTICIPANTS: A total of 6152 participants were selected by stratified cluster-sampling. MAIN OUTCOME MEASURES: Participants completed demographic and dietary questionnaires and underwent physical and thyroid ultrasound examinations. Serum samples were analyzed for thyroid function parameters and selenium concentration. Serum selenium was compared between different demographic, dietary, and lifestyle categories in the two counties. The relationship between selenium status, dietary factors, and pathological thyroid conditions was explored by logistic regression. RESULTS: Complete data sets were available from 3038 adequate-selenium participants and 3114 low-selenium participants in whom median (interquartile range) selenium concentrations differed almost 2-fold (103.6 [79.7, 135.9] vs 57.4 [39.4, 82.1] µg/L; P = .001). The prevalence of pathological thyroid conditions (hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and enlarged thyroid) was significantly lower in the adequate-selenium county than in the low-selenium county (18.0 vs 30.5%; P < .001). Higher serum selenium was associated with lower odds ratio (95% confidence interval) of autoimmune thyroiditis (0.47; 0.35, 0.65), subclinical hypothyroidism (0.68; 0.58, 0.93), hypothyroidism (0.75; 0.63, 0.90), and enlarged thyroid (0.75; 0.59, 0.97). CONCLUSIONS: Low selenium status is associated with increased risk of thyroid disease. Increased selenium intake may reduce the risk in areas of low selenium intake that exist not only in China but also in many other parts of the world.

Regulatory T cells in B-cell-deficient and wild-type mice differ functionally and in expression of cell surface markers.

NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) with chronic inflammation of thyroids by T and B cells. B-cell deficient (B(-/-) ) mice are resistant to SAT but develop SAT if regulatory T (Treg) cells are transiently depleted. We established a transfer model using splenocytes from CD28(-/-)  B(-/-) mice (effector cells and antigen-presenting cells) cultured with or without sorted Treg cells from Foxp3-GFP wild-type (WT) or B(-/-) mice. After transfer to mice lacking T cells, mice given Treg cells from B(-/-) mice had significantly lower SAT severity scores than mice given Treg cells from WT mice, indicating that Treg cells in B(-/-) mice are more effective suppressors of SAT than Treg cells in WT mice. Treg cells from B(-/-) mice differ from WT Treg cells in expression of CD27, tumour necrosis factor receptor (TNFR) II p75, and glucocorticoid-induced TNFR-related protein (GITR). After transient depletion using anti-CD25 or diphtheria toxin, the repopulating Treg cells in B(-/-) mice lack suppressor function, and expression of CD27, GITR and p75 is like that of WT Treg cells. If B(-/-) Treg cells develop with B cells in bone marrow chimeras, their phenotype is like that of WT Treg cells. Addition of B cells to cultures of B(-/-) Treg and T effector cells abrogates their suppressive function and their phenotype is like that of WT Treg cells. These results establish for the first time that Treg cells in WT and B(-/-) mice differ both functionally and in expression of particular cell surface markers. Both properties are altered after transient depletion and repopulation of B(-/-) Treg cells, and by the presence of B cells during Treg cell development or during interaction with effector T cells.

Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies.

CONTEXT: Euthyroid thyroid peroxidase (TPO-Ab)-positive subjects are at risk for progression to subclinical and overt autoimmune hypothyroidism. Previous studies have shown a decrease in TPO-Ab and improvement of quality-of-life (QoL) in L-T4-treated hypothyroid patients upon selenium supplementation. OBJECTIVES: To evaluate in euthyroid TPO-Ab-positive women without thyroid medication whether selenite decreases TPO-Ab and improves QoL. DESIGN: Randomized, placebo-controlled, double-blind study. PATIENTS AND METHODS: Euthyroid (TSH 0·5-5·0 mU/l, FT4 10-23 pm) women with TPO-Ab ≥ 100 kU/l were randomized to receive 200 mcg sodium selenite daily (n = 30) or placebo (n = 31) for 6 months. TSH, FT4, TPO-Ab, selenium (Se), selenoprotein P (SePP) and QoL were measured at baseline, 3, 6 and 9 months. RESULTS: There were no differences in baseline characteristics between the Se group and the placebo group. During selenite supplementation, serum Se and SePP did not change in the placebo group, but increased in the Se group. TPO-Ab and TSH did not change significantly in any group. TPO-Ab in the Se group were 895 (130-6800) at baseline, 1360 (60-7050) kU/l at 6 months, in the placebo group 1090 (120-9200) and 1130 (80-9900) kU/l, respectively (median values with range). TSH in the Se group was 2·1 (0·5-4·3) at baseline, 1·7 (0·0-5·3) mU/l at 6 months, in the placebo group 2·4 (0·7-4·4) and 2·5 (0·2-4·3) mU/l, respectively. QoL was not different between the groups. CONCLUSION: Six months selenite supplementation increased markers of selenium status but had no effect on serum TPO-Ab, TSH or quality-of-life in euthyroid TPO-Ab-positive women.

Effects of green tea polyphenols on iodide-induced autoimmune thyroiditis in nonobese diabetic mice.

Because green tea polyphenols (GTPs) possess anti-inflammatory properties and are effective in inhibiting autoimmune diseases in experimental settings, we examined whether GTPs prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic (NOD) mice, an animal model of Hashimoto's thyroiditis (HT). Mice were given 0.05% iodide water or iodide water supplemented with 0.2% GTPs for 8 weeks. GTPs administration led to an enhanced production of interleukin-10 by concanavalin A-stimulated splenocytes but did not interfere with thyroiditis development. Serum thyroxine levels were not influenced by GTPs. Our data suggest that administration of GTPs may not be an effective strategy for the prevention of HT.

The prevalence of autoimmune thyroiditis after universal salt iodisation in Sri Lanka.

INTRODUCTION: Sri Lanka is endemic for goiters. Iodine deficiency is thought to be the main cause. The global iodisation programme was implemented in the country in 1995. Several studies done in school children have shown a reduction in the goiter prevalence (3.8%) in the initial post iodisation period. An island wide, community based study was carried out to study the prevalence of goiters. METHODS: A multistage cluster sampling method was used. Examination of goiters was done by two trained investigators and graded according to the WHO grading. Fine needle aspiration cytology of the goitres was also undertaken in the field. A sample of urine was collected from all participants. In a random sample of 153 individuals with a goiter, serum was checked for anti thyroid peroxidase antibodies. RESULTS: Out of 5200 individuals screened, 426 had a clinically detectable goiter. Adjusted prevalence rate was 6.8%. Both serological and cytological evidence of autoimmune thyroiditis was seen in 19.6% of goiters. Mean urinary iodine concentration was 235 µg/l range 11.1 - 425 µg/l). Association between elevated antithyroperoxidase antibodies and median urinary iodine concentration was significant. CONCLUSION: Goiter prevalence in Sri Lanka has increased after an initial drop following the iodisation. A significant proportion of goiters is due to AIT. Urinary excretion of Iodine in the community is high and has a positive correlation with the prevalence of aTPO anti vodies. Increase in AIT due to a high Iodine intake may account for the rise in goiter prevalence.

Moderate alcohol consumption may protect against overt autoimmune hypothyroidism: a population-based case-control study.

OBJECTIVE: Alcohol consumption is an important protective risk factor for many autoimmune diseases. We wished to study the association between alcohol consumption and autoimmune hypothyroidism. DESIGN: Population-based, case-control study, 1997-2001, Denmark. METHODS: Patients with newly diagnosed autoimmune overt hypothyroidism (n=140) were prospectively identified in a population (2 027 208 person-years of observation), and their matched controls with normal thyroid function (n=560) were recruited simultaneously from the same population. Participants gave information on alcohol intake, smoking, previous diseases, education, and family history of hypothyroidism. The association between alcohol intake and development of hypothyroidism was analyzed in conditional regression models. RESULTS: Hypothyroid cases had reported a lower alcohol consumption than controls (median units of alcohol (12 g) per week: 3 vs 5, P=0.002). In a multivariate regression model, alcohol consumption was associated with a reduction in risk for development of overt autoimmune hypothyroidism. Odds ratios (95% confidence interval) compared with the reference group with a recent (last year) consumption of 1-10 units of alcohol per week were as follows: 0 units/week, 1.98 (1.21-3.33); 11-20 units/week, 0.41 (0.20-0.83); and ≥21 units/week, 0.90 (0.41-2.00). Similar results were found for maximum previous alcohol consumption during a calendar year. No interaction was found with type of alcohol consumed (wine vs beer), sex, or region of inhabitancy. CONCLUSIONS: Alcohol consumption seems to confer considerable protection against development of overt autoimmune hypothyroidism irrespective of sex and type of alcohol consumed.

Induction of immune tolerance in mice with a novel mucosal nanoemulsion adjuvant and self-antigen.

AIM: The aim of this study was to investigate the impact of a novel nanoemulsion (NE) adjuvant, a soybean oil emulsion, on autoimmune response. To this end, we used murine thyroglobulin (mTg)-induced experimental autoimmune thyroiditis in mice as a study model. MATERIALS & METHODS: Mice received NE or NE + mTg by nasal delivery. At 1 week after the second nasal delivery of NE with or without mTg, all mice were immunized with mTg and lipopolysaccharides to induce experimental autoimmune thyroiditis. RESULTS: Compared with controls, mTg-NE-treated mice had much more antigens accumulated in the nasal passage and thymus and developed a milder form of thyroiditis. This was accompanied by an increase in IL-10, IL-17 and reduced IFN-γ. The production of anti-mTg antibodies was significantly decreased in mTg-NE-treated mice. The percentage of Tregs in cervical lymph nodes was higher in mTg-NE-treated mice than NE-treated mice. Furthermore, Foxp3 and TGF-ß levels were prominently enhanced in mTg-NE-treated mice. CONCLUSION: This study indicates that a low dose of mTg in NE can significantly enhance antigen uptake and Tregs, resulting in inhibition of experimental autoimmune thyroiditis development.

Transient depletion of B cells in young mice results in activation of regulatory T cells that inhibit development of autoimmune disease in adults.

B-cell depletion therapy can be effective for treating B-cell lymphomas as well as many human and murine autoimmune diseases. B-cell-deficient mice are normally resistant to spontaneous autoimmune thyroiditis (SAT), but they develop SAT if regulatory T cells are transiently depleted during the first 3-6 weeks after birth. This was also a critical time when B-cell depletion effectively inhibited development of SAT in adult mice. The current study was undertaken to test the hypothesis that transient depletion of B cells using anti-CD20 would be sufficient to suppress SAT if B cells were depleted early in life and that inhibition of SAT would be due to the activity of Treg that functioned most effectively when B cells were absent or low. The results presented here support this hypothesis and indicate that development of autoimmune disease in adults is effectively inhibited when anti-CD20 is administered 1-3 weeks after birth. After 3 weeks, transient B-cell depletion is no longer effective, and B-cell depletion must be maintained to effectively suppress autoimmune disease. B-cell depletion in 1- to 3-week-old mice depletes all B-cell subsets, whereas B-cell depletion initiated in adults spares many marginal zone B cells. Following early B-cell depletion, splenic Treg increase in number, and depletion of Treg reverses the inhibitory effect of anti-CD20 on disease development. Early transient depletion of B cells could be useful for preventing autoimmune disease in individuals at high risk for developing autoimmune diseases as adults.

Effects of synthetic retinoid Am80 on iodide-induced autoimmune thyroiditis in nonobese diabetic mice.

We examined whether a synthetic retinoid Am80 prevented the development of autoimmune thyroiditis in iodide-treated nonobese diabetic mice, an animal model of Hashimoto's thyroiditis (HT). Am80 (0, 0.1 or 1 mg/kg/day) was orally administered in feed during the 8-week iodide treatment. While iodide ingestion effectively induced thyroiditis, Am80 administration failed to interfere with thyroiditis development and serum anti-thyroglobulin antibody levels regardless of the dose of the retinoid. Splenic T cell numbers, splenocyte proliferation and interferon-γ production were decreased in the Am80-treated mice. Our data suggest that Am80 is not a candidate for use in the prevention of HT.

The sphingosine 1-phosphate receptor modulator FTY720 prevents iodide-induced autoimmune thyroiditis in non-obese diabetic mice.

FTY720 is an immunomodulator that alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. This compound has been shown to be effective in suppressing autoimmune diseases in experimental and clinical settings. In the present study, we tested whether FTY720 prevented autoimmune thyroiditis in iodide-treated non-obese diabetic (NOD) mice, a model of Hashimoto's thyroiditis (HT) in humans. Mice were given 0.05% iodide water for 8 weeks, and this treatment effectively induced thyroiditis. Iodide-treated mice were injected intraperitoneally with either saline or FTY720 during the iodide treatment. FTY720 clearly suppressed the development of thyroiditis and reduced serum anti-thyroglobulin antibody levels. The number of circulating lymphocytes and spleen cells including CD4(+) T cells, CD8(+) T cells, and CD4(+)Foxp3(+) T cells was decreased in FTY720-treated mice. Our results indicate that FTY720 has immunomodulatory effects on iodide-induced autoimmune thyroiditis in NOD mice and may be a potential candidate for use in the prevention of HT.

Transgenic expression of TGF-beta on thyrocytes inhibits development of spontaneous autoimmune thyroiditis and increases regulatory T cells in thyroids of NOD.H-2h4 mice.

Transgenic NOD.H-2h4 mice expressing TGF-beta under control of the thyroglobulin promoter were generated to assess the role of TGF-beta in the development of thyrocyte hyperplasia. In contrast to nontransgenic littermates, which develop lymphocytic spontaneous autoimmune thyroiditis (L-SAT), all TGF-beta transgenic (Tg) mice given NaI water for 2-7 mo developed thyroid lesions characterized by severe thyroid epithelial cell hyperplasia and proliferation, with fibrosis and less lymphocyte infiltration than in nontransgenic mice. Most Tg mice produced less anti-mouse thyroglobulin autoantibody than did wild type (WT) mice. T cells from Tg and WT mice were equivalent in their ability to induce L-SAT after transfer to SCID or TCRalpha(-/-) mice. WT lymphocytes could transfer experimental autoimmune thyroiditis or L-SAT to Tg mice, indicating that the transgenic environment did not prevent migration of lymphocytes to the thyroid. Thyroids of Tg mice had higher frequencies of Foxp3(+) regulatory T cells (Tregs) compared with nontransgenic WT mice. Transient depletion of Tregs by anti-CD25 resulted in increased infiltration of inflammatory cells into thyroids of transgenic mice. Treg depletion also resulted in increased anti-mouse thyroglobulin autoantibody responses and increased expression of IFN-gamma and IFN-gamma-inducible chemokines in thyroids of Tg mice. The results suggest that spontaneous autoimmune thyroiditis is inhibited in mice expressing transgenic TGF-beta on thyrocytes, at least in part, because there is an increased frequency of Tregs in their thyroids.