title: A physiologic function for p-glycoprotein (MDR-1) during the migration of dendritic cells from skin via afferent lymphatic vessels.
abstract: P-glycoprotein (MDR-1) is a well-known transporter that mediates efflux of chemotherapeutic agents from the intracellular milieu and thereby contributes to drug resistance. MDR-1 also is expressed by nonmalignant cells, including leukocytes, but physiologic functions for MDR-1 are poorly defined. Using an initial screening assay that included >100 mAbs, we observed that neutralizing mAbs MRK16, UIC2, and 4E3 against MDR-1 specifically and potently blocked basal-to-apical transendothelial migration of mononuclear phagocytes, a process that may mimic their migration into lymphatic vessels. Antagonists of MDR-1 then were used in a model of authentic lymphatic clearance. In this model, antigen-presenting dendritic cells (DC) migrate out of explants of cultured human skin and into the culture medium via dermal lymphatic vessels. DC and T cells derived from skin expressed MDR-1 on their surfaces. Addition of anti-MDR-1 mAbs MRK16, UIC2, or the MDR-1 antagonist verapamil to skin explants at the onset of culture inhibited the appearance of DC, and accompanying T cells, in the culture medium by approximately 70%. Isotype-matched control mAbs against other DC molecules including CD18, CD31, and major histocompatibility complex I did not block. In the presence of MDR-1 antagonists, epidermal DC were retained in the epidermis, in contrast to control conditions. In summary, this work identifies a physiologic function for MDR-1 during the mobilization of DC and begins to elucidate how these critical antigen-presenting cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated immunity.
authors.affiliation: Department of Pathology, Cornell University Medical College, 1300 York Avenue, New York, NY 10021, USA. GJRandolph@mail.med.cornell.edu
authors.forename: G J
authors.initials: GJ
authors.lastname: Randolph
authors.forename: S
authors.initials: S
authors.lastname: Beaulieu
authors.forename: M
authors.initials: M
authors.lastname: Pope
authors.forename: I
authors.initials: I
authors.lastname: Sugawara
authors.forename: L
authors.initials: L
authors.lastname: Hoffman
authors.forename: R M
authors.initials: RM
authors.lastname: Steinman
authors.forename: W A
authors.initials: WA
authors.lastname: Muller
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008208:Lymphatic System / Q000166:cytology* / Q000502:physiology*; D012867:Skin / Q000098:blood supply / Q000166:cytology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1