title: Autoimmune diabetes is suppressed by transfer of proinsulin-encoding Gr-1+ myeloid progenitor cells that differentiate in vivo into resting dendritic cells.
abstract: 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-beta1, 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(+)/CD86(lo) immature DCs. After transfer, Gr-1(+) myeloid cells acquired the characteristics of resting DCs (CD11c(+)/MHC classII(int)/CD86(lo)/CD40(lo)). 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.
authors.affiliation: Division of Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, 3050 Victoria, Australia.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
authors.forename: Janine M
authors.initials: JM
authors.lastname: Ritchie
authors.forename: Lynelle K
authors.initials: LK
authors.lastname: Jones
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007108:Immune Tolerance; D051379:Mice; D016688:Mice, Inbred NOD; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011384:Proinsulin / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011384:Proinsulin