Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes

Human clinical trials in type 1 diabetes (T1D) patients are underway using mesenchymal stem cells (MSC) without prior validation in a mouse model for the disease. In response to this void, we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in non-obese diabetic (NOD) mice. In comparison to NOD-, BALB/c-MSC express higher levels of the negative costimulatory molecule PD-L1 and promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e. NOR or BALB/c), but not from NOD mice, conferred disease protection when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC resulted in reversal of hyperglycemia in 90% of NOD mice (p=0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit, and in fact soft tissue and visceral tumors were uniquely observed in this setting (i.e. no tumors were present with BALB/c- or NOR-MSC transfer). These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and potentially, other autoimmune disorders.

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Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, La Rosa S, Selig M, Godwin J, Law K, Placidi C, Smith RN, Capella C, Rodig S, Adra CN, Atkinson M, Sayegh MH, Abdi R