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Hematopoietic Mixed Chimerism Derived From Allogeneic Embryonic Stem Cells Prevents Autoimmune Diabetes Mellitus In Nod Mice.

Verda L, An Kim D, Ikehara S, Statkute L, Bronesky D, Petrenko Y, Oyama Y, He X, Link C, Vahanian NN, Burt RK

Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.

Embryonic stem cell (ESC)-derived hematopoietic stem cells (HSC), unlike HSC harvested from the blood or marrow, are not contaminated by lymphocytes. We therefore evaluated whether ESC-derived HSC could produce islet cell tolerance, a phenomenon termed graft versus autoimmune (GVA) without causing the usual allogeneic hematopoietic stem cell transplant (HSCT) complication - graft versus host disease (GVHD). Herein, we demonstrate that ESC-derived HSC may be used to prevent autoimmune diabetes mellitus in NOD mice without GVHD or other adverse side effects. ESC were cultured in vitro to induce differentiation toward HSC, selected for c-kit expression, and injected either intravenous (IV) or intra bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine out of 10 mice from the IBM group and 5 out of 8 from the IV group did not become hyperglycemic, in contrast to the control group, in which 8 of 9 mice developed end-stage diabetes. All mice with > 5% donor chimerism remained free of diabetes and insulitis that was confirmed by histology. Splenocytes from transplanted mice were unresponsive to GAD65, a diabetic specific auto-antigen, but responded normally to 3rd party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, in our knowledge, of ESC-derived HSC cells treating disease in an animal model.

Published 2 November 2007 in Stem Cells.
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