Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Abstract

Almost all cases of hyperthyroidism in children result from Graves' disease (GD). Recent studies have confirmed a significant role of T regulatory cells (Tregs) in the development of autoimmune diseases. However, the interactions between T cell responses and Treg proliferation in GD are still poorly understood. The aim of this study was to assess the proliferation of Treg cells (Tregs) and CD3+ T lymphocytes isolated from 50 children with GD before and after treatment with the thyreostatic drug methimazole (MMI). The proliferation rates, measured by methyl-3H-thymidyne incorporation, of CD3+ cells and Tregs stimulated with mitogen phorbol 12-myristate 13-acetate (PMA) were compared with those of unstimulated cells. The proliferation rates of both PMA-stimulated and unstimulated CD3+ cells prior to treatment with MMI were significantly higher than after treatment. Simultaneously, the proliferation rates of both PMA-stimulated and unstimulated Tregs were significantly lower before MMI treatment. Moreover, we observed higher cell proliferation rates of unstimulated and PMA-stimulated Tregs before the initiation of MMI therapy and after treatment in patients who had no relapse of hyperthyroidism. There was a positive correlation between the CD3+ cells proliferation rate before MMI treatment and fT3, as well as fT4 concentration in peripheral blood. The proliferation rates of CD3+ T cells before and after MMI treatment positively correlated with the TSI index. Thus, children suffering from Graves' disease presented lower Tregs proliferative potential compared with CD3+ T cells. Cocultures of CD3+ T cells and Tregs showed that Tregs were not capable of efficiently inhibiting the proliferation of CD3+ T cells in GD patients. Conclusions. MMI treatment reduced the proliferative activity of CD3+ T cells in pediatric GD patients and increased the proliferation rate of Tregs. We suggest that Treg cells that are partly dysfunctional in GD disease are probably suppressed by CD3+ T cells and that methimazole exerts some immunomodulatory effects.

Impaired immune regulation after radioiodine therapy for Graves’ disease and the protective effect of Methimazole

“…It has recently been demonstrated that ATD could normalize circulating Treg frequency in G patients [10,11,25]. Our results extend these data and demonstrated that an ATD pretreatment moderate the immune changes induced by RAI therapy: less variation of Treg frequency, a trend to less defective Treg function and restoration of normal levels of suppressive cytokines.…”

“…For example, in GD patients taking methimazole, a decrease in TSHR-Ab levels [24] and an increase in peripheral activated Treg [11,25] were described.…”

Decreased Frequencies of Peripheral Blood CD4+CD25+CD127–Foxp3+ in Patients with Graves’ Disease and Graves’ Orbitopathy: Enhancing Effect of Insulin Growth Factor-1 on Treg Cells

“…Klatka et al also demonstrated that co-cultures of CD3 + T cells and Tregs showed that Tregs were not capable of efficiently inhibiting the proliferation of CD3 + T cells in GD patients. In conclusion, the authors suggest that Treg cells are partly dysfunctional in GD disease and are probably suppressed by CD3 + T cells and that methimazole exerts some immunomodulatory effect [22].…”

“…Recently, decreased frequencies of Tregs in PBMCs of the GD patients [20][21][22] and GO patients [23] compared vs. the normal subjects were demonstrated. Bossowski et al found in untreated children with GD and Hashimoto thyroiditis (HT) the significant decrease in CD4 + Foxp3 and CD4 + CD25 high T lymphocytes compared to the healthy controls [20].…”

Percentage and function of CD4+CD25+ regulatory T cells in patients with hyperthyroidism

“…Tregs account for approximately 5–10% of peripheral blood (PB) CD4 T cells. Tregs include two subtypes: Natural Tregs (nTregs; primarily refers to Tregs formed in the embryo/newborn thymus, also described as thymus Tregs or tTregs); and inducible Tregs (iTregs; predominantly induced in vitro , also termed PB Tregs or pTregs) ( 3 ). Recent studies indicated that CD4 + CD25 + Tregs were significant in various types of autoimmune disease ( 4 , 5 ), and CD4 + CD25 + Treg abnormalities may contribute to the occurrence and progression of hyperthyroidism ( 6 ).…”