title: Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation.
abstract: Costimulation-deficient dendritic cells (DCs) prevent autoimmune disease in mouse models. However, autoimmune-prone mice and humans fail to control expansion of peripheral autoreactive effector memory T cells (T(EMs)), which resist immunoregulation by costimulation-deficient DCs. In contrast, activation of DC costimulation may be coupled with regulatory capacity. To test whether costimulatory DCs control T(EMs) and attenuate established autoimmune disease, we used RelB-deficient mice, which have multiorgan inflammation, expanded peripheral autoreactive T(EMs), and dysfunctional Foxp3(+) regulatory T cells (Tregs) cells and conventional DCs. T(EMs) were regulated by Foxp3(+) Tregs when costimulated by CD3/CD28-coated beads or wild-type DCs but not DCs deficient in RelB or CD80/CD86. After transfer, RelB and CD80/CD86-sufficient DCs restored tolerance and achieved a long-term cure of autoimmune disease through costimulation of T(EM) and Foxp3(+) Treg IFN-γ production, as well as induction of IDO by host APCs. IDO was required for regulation of T(EMs) and suppression of organ inflammation. Our data challenge the paradigm that costimulation-deficient DCs are required to regulate established autoimmune disease to avoid T(EM) activation and demonstrate cooperative cross-talk between costimulatory DCs, IFN-γ, and IDO-dependent immune regulation. IFN-γ and IDO activity may be good surrogate biomarkers measured against clinical efficacy in trials of autoimmune disease immunoregulation.
authors: University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
authors: Brendan J
authors: BJ
authors: O'Sullivan
authors: Saparna
authors: S
authors: Pai
authors: Shayna
authors: S
authors: Street
authors: Xiayou
authors: X
authors: An
authors: Kelli P A
authors: KP
authors: MacDonald
authors: Michele
authors: M
authors: Wong
authors: Geoffrey
authors: G
authors: Strutton
authors: Steve
authors: S
authors: Gerondakis
authors: Raymond J
authors: RJ
authors: Steptoe
authors: Barbara Fazekas
authors: BF
authors: de St Groth
authors: Geoffrey R
authors: GR
authors: Hill
authors: Ranjeny
authors: R
authors: Thomas
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D018189:Immunomagnetic Separation; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D051841:Transcription Factor RelB / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: C497594:Relb protein, mouse; D051841:Transcription Factor RelB