title: Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells.
abstract: Regulatory T cell (Treg)-based therapy is a promising approach to treat many immune-mediated disorders such as autoimmune diseases, organ transplant rejection, and graft-versus-host disease (GVHD). Challenges to successful clinical implementation of adoptive Treg therapy include difficulties isolating homogeneous cell populations and developing expansion protocols that result in adequate numbers of cells that remain stable, even under inflammatory conditions. We investigated the potential of discarded human thymuses, routinely removed during pediatric cardiac surgery, to be used as a novel source of therapeutic Tregs. Here, we show that large numbers of FOXP3(+) Tregs can be isolated and expanded from a single thymus. Expanded thymic Tregs had stable FOXP3 expression and long telomeres, and suppressed proliferation and cytokine production of activated allogeneic T cells in vitro. Moreover, expanded thymic Tregs delayed development of xenogeneic GVHD in vivo more effectively than expanded Tregs isolated based on CD25 expression from peripheral blood. Importantly, in contrast to expanded blood Tregs, expanded thymic Tregs remained stable under inflammatory conditions. Our results demonstrate that discarded pediatric thymuses are an excellent source of therapeutic Tregs, having the potential to overcome limitations currently hindering the use of Tregs derived from peripheral or cord blood.
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: I E
authors.initials: IE
authors.lastname: Dijke
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R E
authors.initials: RE
authors.lastname: Hoeppli
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Ellis
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Pearcey
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A N
authors.initials: AN
authors.lastname: McMurchy
authors.affiliation: Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Boer
authors.affiliation: Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, the Netherlands.
authors.forename: A M A
authors.initials: AM
authors.lastname: Peeters
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Aubert
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Larsen
authors.affiliation: Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.|Department of Surgery, University of Alberta, Edmonton, AB, Canada.
authors.forename: D B
authors.initials: DB
authors.lastname: Ross
authors.affiliation: Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.|Department of Surgery, University of Alberta, Edmonton, AB, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Rebeyka
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Department of Internal Medicine, Erasmus MC Medical Center, Rotterdam, the Netherlands.
authors.forename: C C
authors.initials: CC
authors.lastname: Baan
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: M K
authors.initials: MK
authors.lastname: Levings
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.|Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada.|Department of Surgery, University of Alberta, Edmonton, AB, Canada.
authors.forename: L J
authors.initials: LJ
authors.lastname: West
mesh_terms: D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D002648:Child; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology / Q000628:therapy*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D059505:Telomere Homeostasis; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit