title: Suppression of IL-7-dependent Effector T-cell Expansion by Multipotent Adult Progenitor Cells and PGE2.
abstract: T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients.
authors.affiliation: Department of Immunobiology, King's College London, London, UK. Electronic address: James.reading@kcl.ac.uk.
authors.forename: James L
authors.initials: JL
authors.lastname: Reading
authors.affiliation: Regenesys Ltd., Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Vaes
authors.affiliation: Department of Immunobiology, King's College London, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hull
authors.affiliation: Department of Immunobiology, King's College London, London, UK.
authors.forename: Shereen
authors.initials: S
authors.lastname: Sabbah
authors.affiliation: Department of Immunobiology, King's College London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hayday
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Wang
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: DiPiero
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Lehman
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Jen M
authors.initials: JM
authors.lastname: Taggart
authors.affiliation: Department of Biology, Institute of Immunology, National University of Ireland, Maynooth, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Carty
authors.affiliation: Department of Biology, Institute of Immunology, National University of Ireland, Maynooth, Ireland.
authors.forename: Karen
authors.initials: K
authors.lastname: English
authors.affiliation: Regenesys Ltd., Leuven, Belgium.
authors.forename: Jef
authors.initials: J
authors.lastname: Pinxteren
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Deans
authors.affiliation: Athersys Inc, Cleveland, Ohio, USA.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Ting
authors.affiliation: Department of Immunobiology, King's College London, London, UK; NIHR Biomedical Research Centre at Guy's & St Thomas' NHS Foundation Trust and King's College London, London, UK.
authors.forename: Timothy I M
authors.initials: TIM
authors.lastname: Tree
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000276:immunology / Q000502:physiology*; D015551:Autoimmunity; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology*; D006084:Graft Rejection; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D008212:Lymphocyte Depletion / Q000009:adverse effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000502:physiology*; D039902:Multipotent Stem Cells / Q000276:immunology / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014184:Transplantation, Homologous / Q000379:methods; D055815:Young Adult; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D015232:Dinoprostone; D053583:Interleukin-1beta; D015851:Interleukin-7; D009687:Nuclear Proteins; D050826:Suppressor of Cytokine Signaling Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C508585:IL1B protein, human; C508605:IL7 protein, human; C106643:SOCS2 protein, human