Human Mesenchymal Stem Cells Modulate Cellular Immune Response to Islet Antigen Glutamic Acid Decarboxylase in Type 1 Diabetes

Abstract

These results provide evidence that human MSCs abrogate in vitro a proinflammatory T helper type 1 response to an islet antigenic stimulus in type 1 diabetes. MSCs induce IL-4-producing cells, suggesting a possible switch to an antiinflammatory T helper type 2 signaling of T cells.

Human mesenchymal stem cells and derived extracellular vesicles induce regulatory dendritic cells in type 1 diabetic patients

“…Participants and DC generation Peripheral blood mononuclear cells (PBMCs) were obtained from nine white patients with recent-onset type 1 diabetes on the basis of a positive IFN-γ response to glutamic acid decarboxylase (GAD65; stimulation index [SI] ≥3; Table 1) by enzyme-linked immunosorbent spot (ELISPOT) analysis as previously described [12,21]. CD14 + monocytes were isolated by positive selection (CD14 microbeads, Miltenyi Biotec, Bergisch Gladbach, Germany) and CD14…”

“…MSCs have emerged in recent years as a safe, promising treatment strategy for autoimmune diseases, including type 1 diabetes [11,12]. Originally performed in animal studies, this cellular intervention has recently been translated to patients with recent-onset diabetes [13].…”

Perspectives of Cell Therapy in Type 1 Diabetes

“…Lymphocyte activation is extremely complex and it is likely that several mechanisms are involved in the MSC-mediated immunesuppression and that the specific factors may depend on the lymphocyte population tested, the stimulus used, the timing of analysis and the context of the immune disease. Further, inhibition of PGE 2 production abrogated the MSC-mediated IFN- suppression, indicating that PGE 2 secretion plays a key role in MSC-mediated immune effects, and the contact between MSC and PBMC enhances the production of prostaglandin E2 (Zanone et al, 2010). This observation suggests the requirement of both soluble factors and cell-contact in line with the interpretation that the immunemodulatory effects of MSC might require an initial cell-contact phase (Krampera et al, 2003).…”

“…The mechanisms of MSC interaction with the immune system cells are still controversial (van Laar & Tyndall, 2006;Abdi et al, 2008), and include reduction of the expression of lymphocyte activation markers, change of the cytokine profile of dendritic cells, naive and activated T cells and NK cells to an anti-inflammatory phenotype, and increase of the regulatory T cell population (Aggarwal & Pittenger, 2005;. In the reported study in type 1 diabetes, MSC induced in peripheral blood mononuclear cells (PBMC) of responder patients IL-4 producing cells and IL-4 secretion, suggesting a possible switch to an anti-inflammatory Th2 signalling of T cells (Zanone et al, 2010). Increased IL-4 secretion has been shown in studies of MSC cocultured with subpopulations of PHA-stimulated immune cells (Aggarwal & Pittenger, 2005) but not in studies of T cells activated by encephalitogenic peptide (Zappia et al, 2005).…”

“…Studies on the immunemodulatory potential of MSC in human type 1 diabetes are still lacking but it has been reported their regenerative potential in diabetic NOD/SCID mice leading to an increased number of pancreatic islets and  cells (R.H. Lee et al, 2006). We recently demonstrated that human allogenic bone marrow derived MSC can abrogate in vitro a pro-inflammatory Th1 response to islet antigen GAD in new onset type 1 diabetes, by impairing the production of IFN- and by inducing anti-inflammatory IL-4 production (Zanone et al, 2010). These data stimulate further studies on MSC immunemodulation in diabetes and open a perspective for immune-intervention strategies.…”