BM stromal cells ameliorate experimental autoimmune myasthenia gravis by altering the balance of Th cells through the secretion of IDO

Abstract

In addition to their capacity to differentiate, BM stromal cells (BMSC) have immunosuppressive qualities that make them strong candidates for use in cell therapy against human autoimmune diseases. We studied the immunoregulatory activities of BMSC on experimental autoimmune myasthenia gravis (EAMG) in vitro and in vivo. Intravenous administration of syngenic BMSC to EAMG-model rats on the day of their second immunization was effective in ameliorating the pathological features of the disease. In vitro, the proliferative ability of T cells or B cells from EAMG rats was inhibited when they were cocultured with BMSC at proper ratios. This inhibitory effect was at least partially dependent on the secretion of IDO. We also determined that the development of EAMG is accompanied by an imbalance among the Th1, Th2, Th17, and Treg cell subsets, and that this can be corrected by the administration of BMSC, which leads to an increase of Th2 (IL-4) and Treg (Foxp3) cells, and a reduction of Th1 (IFN-c) and Th17 (IL-17) cells, through an IDO-dependent mechanism. These results provide further insights into the pathogenesis of MG, EAMG, and other immune-mediated diseases, and support a potential role for BMSC in their treatment.Key words: BM stromal cells . Experimental autoimmune myasthenia gravis . IDO . Th17Supporting Information available online Introduction BM stromal cells (BMSC, also called bone mesenchymal stem cells) are present at low frequency (1/10 4 -1/10 5 ) [1] in the adult BM of many species. They provide a scaffold for hematopoiesis and hematopoietic-cell homeostasis [2] and, under the appropriate conditions, are capable of giving rise to cells of all three germ layers, including osteoblasts, adipocytes, chondrocytes[1], skeletal myocytes [3], and neurons [4]. Their ability to generate multiple mesenchymal lineages makes them a promising candidate for use in strategies directed toward tissue engineering, repair of damaged tissues, and gene therapy [1,3,4]. BMSC have more recently been shown to have the ability to modulate many T-cell [5,6], B-cell [7], NK, and dendritic-cell [8,9] functions, suggesting that they might also for the therapy of immune-mediated disorders. When human MSC are administered in vivo, they can assist hematopoietic engraftment while hampering graft-versus-host disease [2,6,8,10]. Systemic administration of BMSC in mice suffering from EAE, a disease model of multiple sclerosis that is mediated by self-reactive T cells 800results in highly effective disease amelioration associated with a profound suppression of effector T cells and the induction of peripheral tolerance [11]. BMSC may also inhibit the maturation and function of dendritic cells [9,11], suggesting that activated T cells are not the only targets of BMSC. It has been further demonstrated that human MSC can significantly affect the proliferation, differentiation, and chemotactic behavior of normal mature B cells [7]. Though the mechanisms mediating such effects are still not fully understood, it is likely that both cell-tocell c...

Complement and cytokine based therapeutic strategies in myasthenia gravis

“…Also, the proliferative response of T cells in response to AChR stimulation was increased when stimulated by IL-17 in vitro [64e66]. Moreover, treatment with immunosuppressive bone marrow stromal cells or dendritic cells ameliorated EAMG symptoms by shifting the balance from Th1/Th17 dominance towards Th2/Treg dominance [65,66]. A similar balance between regulatory and inflammatory T cells was also observed in a clinical study, in which MG patients with reduced Treg cells showed more severe MG symptoms [67].…”

Allogeneic Tendon-Derived Stem Cells Promote Tendon Healing and Suppress Immunoreactions in Hosts:In VivoModel

“…The low immunogenicity and immunomodulatory effects of MSCs have been well reported. [8][9][10][11][12][13][14][15][16] Ouyang et al reported no apparent lymphocyte infiltration with the use of allogeneic BMSCs for tendon repair, 17,18 although the number of labeled stem cells decreased with time; and the authors suggested that this was related to the tendon remodeling process. 18 No identification of inflammatory cells was done in these previous studies.…”

Indoleamine 2,3-dioxygenase mediates inhibition of virus-specific CD8+ T cell proliferation by human mesenchymal stromal cells

“…Both tryptophan depletion and the presence of its metabolite kynurenine are able to suppress T-cell proliferation [21,22]. Moreover, IDO is also considered to be involved in the generation of regulatory T cells and tolerogenic dendritic cells induced by MSCs [23][24][25]. MSCs do not constitutively express IDO, but interferon-γ (IFN-γ) induces IDO expression in a dose-dependent manner [18].…”