Mesenchymal stromal cells (MSCs) are inherently immunomodulatory through production of inhibiting soluble factors and expression of immunosuppressive cell surface markers. We tested whether activated MSCs qualify for the induction of antigen-specific immune regulation. Bone marrow derived human MSCs were activated by interferon-γ and analyzed for antigen uptake and processing and immune regulatory features including phenotype, immunosuppressive capacity, and metabolic activity. To assess whether activated MSC can modulate adaptive immunity, MSCs were pulsed with islet auto-antigen (GAD65) peptide to stimulate GAD65-specific T-cells. We confirm that inflammatory activation of MSCs increased HLA class II, PD-L1, and intracellular IDO expression, whereas co-stimulatory molecules including CD86 remained absent. MSCs remained locked in their metabolic phenotype, as activation did not alter glycolytic function or mitochondrial respiration. MSCs were able to uptake and process protein. Activated HLA-DR3-expressing MSCs pulsed with GAD65 peptide inhibited proliferation of HLA-DR3-restricted GAD65-specific T-cells, while this HLA class II expression did not induce cellular alloreactivity. Conditioning of antigen-specific T-cells by activated and antigen-pulsed MSCs prevented T-cells to proliferate upon subsequent activation by dendritic cells, even after removal of the MSCs. In sum, activation of MSCs with inflammatory stimuli turns these cells into suppressive cells capable of mediating adaptive regulation of proinflammatory pathogenic T-cells.

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Aims/hypothesis Type 1 diabetes is believed to be an autoimmune disease associated with irreversible loss of insulin secretory function that follows a chronic progressive course. However, it has been speculated that relapsing/remitting disease progression may occur in type 1 diabetes. Methods We report the case of an 18-year-old girl with Graves' disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple islet autoantibodies, presenting with relapsing/remitting hyperglycaemia. Peripheral blood mononuclear cells were analysed for islet autoimmunity. Results There were two instances of hyperglycaemia relapse during CIDP flare-ups that required insulin therapy and remitted after i.v. immunoglobulin (IVIG) therapy improving neurological symptoms. A diagnosis of type 1 diabetes was assigned on the basis of insulin need, HbA 1c and islet autoantibodies. Insulin requirements disappeared following IVIG treatment and peaked during CIDP flare-ups. Pro-and antiinflammatory cytokine responses were noted against islet autoantigens. Conclusions/interpretation We provide clinical evidence of relapsing/remitting type 1 diabetes associated with IVIG treatment and the regulation of islet autoimmunity. Despite sufficient residual beta cell mass, individuals can experience episodes of impaired glycaemia control. This disconnect between beta cell mass and function highlighted by our case may have implications for the use of beta cell function as the primary endpoint for immune intervention trials aiming to protect beta cell mass rather than function. Immune modulation may restore beta cell function and glycaemic control.