856-P: Prevention of Type 1 Diabetes with MSC-EV

Objective: Type 1 diabetes (T1D) is an autoimmune disease characterized by immune cell-mediated destruction of beta cells resulting in loss of insulin production and glucose homeostasis. Mesenchymal stem cells (MSCs) are a heterogeneous population of adult stem cells that can be isolated from many tissues including umbilical cords. Extracellular vehicles (EVs) derived from human MSCs have been proposed to have the potential for restoring immune tolerance and to block the immune/inflammatory attack on beta cells. We examined the ability of human MSC-EV to prevent transfer of T1D in mice. Methods: Adoptive transfer of T1D was performed in 7-week-old female NOD/SCID mice received 10 x 106 splenocytes from 12-week-old female NOD mice, followed 24 hours later with either PBS, 1 x 106 MSCs or 5 x 109 MSC-EVs, two doses each, 7 days apart. Blood glucose was monitored daily, and IPGTT was performed before animal sacrifice. Blood, splenocytes and pancreas were then harvested. Results: Mice treated with EVs or MSCs showed reduction in the development of diabetes. More germane, EV-treated animals fared best with 75% showing no diabetes at 9 weeks post treatment. IPGTT data showed that mice treated with EVs have less rise in blood glucose and faster restoration towards baseline compared to MSC- and PBS-treated animals. Further, these mice showed less overall glucose variability during the test. The splenocytes from EV-treated mice produced significantly less inflammatory cytokines MIP-2, IL-1α and IL-12 and more anti-inflammatory IL-10 compared to splenocytes from PBS-treated mice. FACS analysis found more regulatory CD4/Foxp3 and CD4/CD25/Foxp3 positive T cells in the circulation of EV-treated mice compared to controls. MSC and EV-treated mice displayed more insulin-positive beta cells compared to PBS-treated animals, but density of these cells were less in the MSC than the EV-treated group. Conclusion: MSC-EV therapy can prevent development of T1D more effectively than MSCs, presenting a huge opportunity for patients at risk or having established T1D. Disclosure A.S. Gu: None. A. Bag: None. Y. Ho: None. A. Rao: None. K. Rodriguez: None. L.N. Miao: None. J. Rawson: None. M.I. Husseiny: None. F.R. Kandeel: Advisory Panel; Vertex Pharmaceuticals Incorporated.