Prednisolone Treatment Induces Tolerogenic Dendritic Cells and a Regulatory Milieu in Myasthenia Gravis Patients

Abstract

FOXP3-expressing naturally occurring CD4+CD25high T regulatory cells (Treg) are relevant in the control of autoimmunity, and a defect in this cell population has been observed in several human autoimmune diseases. We hypothesized that altered functions of peripheral Treg cells might play a role in the immunopathogenesis of myasthenia gravis, a T cell-dependent autoimmune disease characterized by the presence of pathogenic autoantibodies specific for the nicotinic acetylcholine receptor. We report in this study a significant decrease in the in vitro suppressive function of peripheral Treg cells isolated from myasthenia patients in comparison to those from healthy donors. Interestingly, Treg cells from prednisolone-treated myasthenia gravis patients showed an improved suppressive function compared with untreated patients, suggesting that prednisolone may play a role in the control of the peripheral regulatory network. Indeed, prednisolone treatment prevents LPS-induced maturation of monocyte-derived dendritic cells by hampering the up-regulation of costimulatory molecules and by limiting secretion of IL-12 and IL-23, and enhancing IL-10. In addition, CD4+ T cells cultured in the presence of such tolerogenic dendritic cells are hyporesponsive and can suppress autologous CD4+ T cell proliferation. The results shown in this study indicate that prednisolone treatment promotes an environment that favors immune regulation rather than inflammation.

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…There are several agents [i.e., rapamycin, vitamin D analogues, granulocyte macrophage colonystimulating factor (GM-CSF); see below] that could be used to improve the function or enhance the numbers of Tregs [82,83]. In addition, a number of currently used immunomodulatory treatments for MG, including corticosteroids and IVIg [84][85][86], have been reported to induce an expansion of Tregs and/or an enhancement in Treg function. A fuller understanding of the mechanisms underlying these effects may be helpful in identifying novel treatment strategies.…”

Regulatory dendritic cells: New targets for cancer immunotherapy

“…34 IDO is the high levels of IL-10, TGFβ, COX-2 and indoleamine-2,3-dioxygenase (IDO). 15 Others describe regDC as immature or semi-mature DC pretreated with IL-10, prednisolone or vitamin D3, [16][17][18][19][20] while some state that regDC are mature DC pretreated with TGFβ, 14 IL-10/TGFβ1 or IL-10/IL-6 ( Table 1). 21,22 Despite the present controversy in characterizing regDC, the role of DC with tolerogenic or immunosuppressive phenotypes in transplantation, allergy, autoimmune and infectious diseases has been repeatedly proven.…”

Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells

“…Data showed that this treatment can affect the production of Th1 or Th17 polarizing cytokines produced by innate immune cells, as well as T-cell capability to respond to these cytokines. 47,48 Furthermore, recent in vitro and in vivo studies showed that glucocorticoids can favor the establishment of pro-tolerogenic conditions. Human DCs treated with glucocorticoids up-regulate the GC-Induced Leucine Zipper protein (GILZ) and differentiate into tolerogenic cells capable of inducing IL-10-producing antigen-specific Tregs.…”