TSG-6 Produced by hMSCs Delays the Onset of Autoimmune Diabetes by Suppressing Th1 Development and Enhancing Tolerogenicity

Abstract

Genetic and immunological screening for type 1 diabetes has led to the possibility of preventing disease in susceptible individuals. Here, we show that human mesenchymal stem/stromal cells (hMSCs) and tumor necrosis factor-α–stimulated gene 6 (TSG-6), a protein produced by hMSCs in response to signals from injured tissues, delayed the onset of spontaneous autoimmune diabetes in NOD mice by inhibiting insulitis and augmenting regulatory T cells (Tregs) within the pancreas. Importantly, hMSCs with a knockdown of tsg-6 were ineffective at delaying insulitis and the onset of diabetes in mice. TSG-6 inhibited the activation of both T cells and antigen-presenting cells (APCs) in a CD44-dependent manner. Moreover, multiple treatments of TSG-6 rendered APCs more tolerogenic, capable of enhancing Treg generation and delaying diabetes in an adoptive transfer model. Therefore, these results could provide the basis for a novel therapy for the prevention of type 1 diabetes.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…There is increasing evidence that HA/IαI/TSG6 complexes have powerful tissue-protecting effects and that the precise organization of the HA matrix in vivo dictates its functional effect (10)(11)(12). Together, these data implicated HA and the islet ECM in the onset of T1D.…”

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

“…TSG-6 exerts its antiinflammatory actions through multiple mechanisms, one of which is the modulation of myeloid cells into a tolerogenic phenotype. In the study by Lee et al, TSG-6 treatment of bone marrow-derived myeloid precursors increased the number of CD11c + B220 + CD8α + cells of plasmacytoid dendritic subtype, and transfer of myeloid cells cultured with TSG-6 delayed the development of autoimmune diabetes in nonobese diabetic mice (35). Therefore, MSCs and their secreted protein TSG-6 may modulate the endogenous immune system through actions on myeloid cells.…”

“…Recently, observations by our group and others identified TSG-6 as being responsible for the beneficial effects of MSCs in the treatment of disease models of the heart (4), cornea (5,19,32), brain (33), lung (34), and pancreas (35). TSG-6 exerts its antiinflammatory actions through multiple mechanisms, one of which is the modulation of myeloid cells into a tolerogenic phenotype.…”

Thinking Outside the Cell: A Key Role for Hyaluronan in the Pathogenesis of Human Type 1 Diabetes

“…Antibody blocking of the HA receptor CD44 conferred resistance to diabetes development, and administration of hyaluronidase partially prevented adoptive transfer of diabetes (96). Human mesenchymal stem cells secreting the HA-binding molecule TSG-6 delayed onset of type 1 diabetes in NOD mice, in part by the suppressive effects of TSG-6 on antigen presentation and cytotoxic T-cell activation (97). Altogether, these studies indicate multiple mechanisms by which HA and associated proteins can regulate events associated with development of type 1 diabetes.…”