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Diabetes 54:434-442, 2005
© 2005 by the American Diabetes Association, Inc.

Autoimmune Diabetes Is Suppressed by Transfer of Proinsulin-Encoding Gr-1+ Myeloid Progenitor Cells That Differentiate In Vivo Into Resting Dendritic Cells

Raymond J. Steptoe, Janine M. Ritchie, Lynelle K. Jones, and Leonard C. Harrison

From the Division of Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

The nature of the T-cell response to antigen is governed by the activation state of the antigen-presenting dendritic cell (DC). Immature or resting DCs have been shown to induce T-cell responses that may protect against the development of autoimmune disease. Effectively harnessing this "tolerogenic" effect of resting DCs requires that it be disease-specific and that activation of DCs by manipulation ex vivo is avoided. We reasoned that this could be achieved by transferring in vivo partially differentiated myeloid progenitor cells encoding a disease-specific autoantigen. With the aim of preventing autoimmune diabetes, we transferred myeloid progenitor cells encoding proinsulin into NOD mice. Bone marrow (BM) was cultured in granulocyte macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-ß1, a cytokine combination that expands myeloid cells but inhibits terminal DC differentiation, to yield Gr-1+/CD11b+/CD11c– myeloid progenitor cells and a minor population of CD11c+/CD11b+/CD86lo immature DCs. After transfer, Gr-1+ myeloid cells acquired the characteristics of resting DCs (CD11c+/MHC classIIint/CD86lo/CD40lo). Gr-1+ myeloid cells generated from transgenic NOD mice that expressed proinsulin controlled by a major histocompatibility complex (MHC) class II promoter, but not from wild-type NOD mice, transferred into 4-week-old female NOD mice significantly suppressed diabetes development. The transfer of DC progenitors encoding a disease-specific autoantigen is, therefore, an effective immunotherapeutic strategy that could be applied to humans.

Address correspondence and reprint requests to Leonard C. Harrison, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, 3050 Victoria, Australia. E-mail: harrison{at}wehi.edu.au

Abbreviations: BM, bone marrow; CFSE, 5(6)-carboxyfluorescein diacetate succinimidyl ester; DC, dendritic cell; FITC, fluorescein isothiocyanate; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; M-CSF R, macrophage colony-stimulating factor receptor; MHC, major histocompatibility complex; rm, recombinant murine; SA, streptavidin; TGF, transforming growth factor; TNF, tumor necrosis factor


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