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EMBRYONIC STEM CELLS

Hematopoietic Mixed Chimerism Derived from Allogeneic Embryonic Stem Cells Prevents Autoimmune Diabetes Mellitus in NOD Mice

^aDivision of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA;
^bFirst Department of Pathology, Transplantation Center, Kansai Medical University, Osaka, Japan;
^cPathology Core Facility, Northwestern University Cancer Center, Chicago, Illinois, USA;
^dNewLink Genetics Corporation, Iowa State University Research Park, Ames, Iowa, USA

Key Words. Embryonic stem cells • Diabetes mellitus • Immune tolerance • Hematopoiesis

Correspondence: Richard K. Burt, M.D., 750 North Lake Shore Drive, ABA Building 6-649, Chicago, Illinois 60611, USA. Telephone: 312-908-0059; Fax: 312-908-0064; e-mail: rburt{at}northwestern.edu

Received April 28, 2006; accepted for publication October 19, 2007.
First published online in STEM CELLS EXPRESS   November 1, 2007.



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 autoimmunity (GVA), without causing the usual allogeneic hematopoietic stem cell transplant 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 i.v. or intra-bone marrow (IBM) into sublethally irradiated NOD/LtJ mice. Nine of 10 mice from the IBM group and 5 of 8 from the i.v. 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, which was confirmed by histology. Splenocytes from transplanted mice were unresponsive to glutamic acid decarboxylase isoform 65, a diabetic-specific autoantigen, but responded normally to third-party antigens. ESC-derived HSC can induce an islet cell tolerizing GVA effect without GVHD. This study represents the first instance, to our knowledge, of ESC-derived HSC cells treating disease in an animal model.

Disclosure of potential conflicts of interest is found at the end of this article.

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