title: P-glycoprotein targeting: a unique strategy to selectively eliminate immunoreactive T cells.
abstract: T lymphocytes have been found to harbor P-glycoprotein (Pgp) and to demonstrate modulation of its ion channel transporter function according to the state of activation of T lymphocytes. We hypothesized that cytotoxic chemicals that are extruded by Pgp could be used to specifically eliminate immunoreactive T-cell populations. In this study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer structurally similar to rhodamine, a dye transported by Pgp, and which becomes highly cytotoxic on activation with visible light to selectively deplete alloreactive T lymphocytes. Stimulation of T cells with mitogens or allogeneic major histocompatibility complex-mismatched cells resulted in the preferential retention of the TH9402 rhodamine-derivative in activated T cells, both CD4+ and CD8+. Photodynamic cell therapy of TH9402-exposed T cells led to the selective elimination of immunoreactive T-cell populations. In addition, this treatment preserved resting T cells and their capacity to respond to third-party cells. Inhibition of Pgp enhanced cellular trapping of the dye in nonactivated T cells and resulted in their depletion after exposure to light. Targeting of Pgp-deficient cells may therefore represent an appealing strategy for the prevention and treatment of graft-versus-host disease and other alloimmune or autoimmune disorders.
authors.affiliation: Division of Hematology-Immunology, Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, Université de Montréal, and Theratechnologies Inc, Montreal, QC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Antonia
authors.initials: A
authors.lastname: Balassy
authors.forename: Mélanie
authors.initials: M
authors.lastname: Barrette
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brochu
authors.forename: Claude
authors.initials: C
authors.lastname: Perreault
authors.forename: Denis Claude
authors.initials: DC
authors.lastname: Roy
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D012235:Rhodamines / Q000493:pharmacokinetics / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017319:Photosensitizing Agents; D012235:Rhodamines; C121365:4,5-dibromorhodamine 123