title: A short pulse of IL-4 delivered by DCs electroporated with modified mRNA can both prevent and treat autoimmune diabetes in NOD mice.
abstract: Bone marrow-derived dendritic cells (DCs) are cells of the immune system that have been used as a tool to boost, modulate, or dampen immune responses. In the context of autoimmunity, DCs can be modified to express immunoregulatory products encoded by transgenes, and used therapeutically in adoptive cellular therapy. DCs that were lentivirally transduced (lt) to express interleukin 4 (IL-4) can significantly delay or prevent the onset of autoimmune diabetes in nonobese diabetic (NOD) mice. However, modifying cells using viral vectors carries the dual risk of oncogenicity or immunogenicity. This study demonstrates that NOD DCs, electroporated with "translationally enhanced" IL-4 mRNA (eDC/IL-4), can be equally efficient therapeutically, despite the reduced amount and shorter duration of IL-4 secretion. Moreover, a single injection of eDC/IL-4 in NOD mice shortly after the onset of hyperglycemia was able to maintain stable glycemia for up to several months in a significant fraction of treated mice. Treatment with eDC/IL-4 boosted regulatory T (Tregs) cell functions and modulated T helper responses to reduce pathogenicity. Thus, treatment with DCs, electroporated with modified IL-4 mRNA to express IL-4 for up to 24 hours, constitutes a viable cellular therapy approach for the regulation of autoimmune diabetes, as a preferred alternative to the use of viral vectors.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305-5166, USA.
authors.forename: Rémi J
authors.initials: RJ
authors.lastname: Creusot
authors.forename: Pearl
authors.initials: P
authors.lastname: Chang
authors.forename: Don G
authors.initials: DG
authors.lastname: Healey
authors.forename: Irina Y
authors.initials: IY
authors.lastname: Tcherepanova
authors.forename: Charles A
authors.initials: CA
authors.lastname: Nicolette
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control* / Q000628:therapy*; D018274:Electroporation; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D015847:Interleukin-4