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

Author:

Verda Larissa1,Kim Duck An1,Ikehara Susumu2,Statkute Laisvyde1,Bronesky Delphine1,Petrenko Yevgeniya1,Oyama Yu1,He Xiang3,Link Charles4,Vahanian Nicholas N.4,Burt Richard K.1

Affiliation:

1. Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

2. First Department of Pathology, Transplantation Center, Kansai Medical University, Osaka, Japan

3. Pathology Core Facility, Northwestern University Cancer Center, Chicago, Illinois, USA

4. NewLink Genetics Corporation, Iowa State University Research Park, Ames, Iowa, USA

Abstract

Abstract 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.

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

Reference23 articles.

1. The non-obese diabetic (NOD) mouse;Leiter;Am J Pathol,1987

2. Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes;LaFace;Diabetes,1989

3. Prevention of type I diabetes in nonobese diabetic mice by allogeneic bone marrow transplantation;Ikehara;Proc Natl Acad Sci U S A,1985

4. Mixed allogeneic chimerism induced by sublethal approach prevents autoimmune diabetes and reverses insulitis in nonobese diabetic (NOD) mice;Li;J Immunol,1996

5. Donor lymphocyte infusion: The use of alloreactive and tumor-reactive lymphocytes for immunotherapy of malignant and nonmalignant diseases with conjunction with allogeneic stem cell transplantation;Slavin;J Hematother Stem Cell Res,2002

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