Autoimmune diabetes is suppressed by transfer of proinsulin-encoding [Gr-1.sup.+] myeloid progenitor cells that differentiate in vivo into resting dendritic cells

Antigen-presenting dendritic cells (DCs) determine the functional properties of the T-cells with which they interact. In the absence of activating signals to DCs, such as those mediated through toll-like receptors [...]
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-β1, a cytokine combination that expands myeloid cells but inhibits terminal DC differentiation, to yield [Gr-1.sup.+]/CD[11b.sup.+]/CD[11c.sup.-] myeloid progenitor cells and a minor population of CD[11c.sup.+]/ CD[11b.sup.+]/CD[86.sup.lo] immature DCs. After transfer, [Gr-1.sup.+] myeloid cells acquired the characteristics of resting DCs (CD[11c.sup.+]/MHC class[II.sup.int]/CD[86.sup.lo]/CD[40.sup.lo]). [Gr-1.sup.+] 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.