title: Photodepletion differentially affects CD4+ Tregs versus CD4+ effector T cells from patients with chronic graft-versus-host disease.
abstract: Even the most potent immunosuppressive drugs often fail to control graft-versus-host disease (GVHD), the most frequent and deleterious posttransplantation complication. We previously reported that photodepletion using dibromorhodamine (TH9402) eliminates T cells from healthy donors activated against major histocompatibility complex-incompatible cells and spares resting T cells. In the present study, we identified photodepletion conditions selectively eradicating endogenous proliferating T cells from chronic GVHD patients, with the concomittant sparing and expansion of CD4(+)CD25(+) forkhead box protein 3-positive T cells. The regulatory T-cell (Treg) nature and function of these photodepletion-resistant cells was demonstrated in coculture and depletion/repletion experiments. The mechanism by which Tregs escape photodepletion involves active P-glycoprotein-mediated drug efflux. This Treg-inhibitory activity is attributable to interleukin-10 secretion, requires cell-cell contact, and implies binding with cytotoxic T-lymphocyte antigen 4 (CTLA-4). Preventing CTLA-4 ligation abrogated the in vitro generation of Tregs, thus identifying CTLA-4-mediated cell-cell contact as a crucial priming event for Treg function. Moreover, the frequency of circulating Tregs increased in chronic GVHD patients treated with TH9402 photodepleted cells. In conclusion, these results identify a novel approach to both preserve and expand Tregs while selectively eliminating CD4(+) effector T cells. They also uncover effector pathways that could be used advantageously for the treatment of patients with refractory GVHD.
authors.affiliation: Division of Hematology-Oncology, Hopital Maisonneuve-Rosemont Research Center, Montreal, QC, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Bastien
authors.forename: Gorazd
authors.initials: G
authors.lastname: Krosl
authors.forename: Cynthia
authors.initials: C
authors.lastname: Therien
authors.forename: Marissa
authors.initials: M
authors.lastname: Rashkovan
authors.forename: Christian
authors.initials: C
authors.lastname: Scotto
authors.forename: Sandra
authors.initials: S
authors.lastname: Cohen
authors.forename: David S
authors.initials: DS
authors.lastname: Allan
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
authors.forename: Denis Claude
authors.initials: DC
authors.lastname: Roy
mesh_terms: D002469:Cell Separation; D002908:Chronic Disease; D002986:Clinical Trials as Topic; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D017319:Photosensitizing Agents / Q000494:pharmacology*; D012235:Rhodamines / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D017319:Photosensitizing Agents; D012235:Rhodamines; C121365:4,5-dibromorhodamine 123