A PHYSIOLOGICAL-FUNCTION FOR P-GLYCOPROTEIN (MDR-1) DURING THE MIGRATION OF DENDRITIC CELLS FROM SKIN VIA AFFERENT LYMPHATIC VESSELS

P-glycoprotein (MDR-1) is a well-known transporter that mediates efflu x of chemotherapeutic agents from the intracellular milieu and thereby contributes to drug resistance. MDR-1 also is expressed by nonmaligna nt cells, including leukocytes, but physiologic functions for MDR-1 ar e poorly defined. Using an initial screening assay that included >100 mAbs, we observed that neutralizing mAbs MRK6, UIC2, and 4E3 against M DR-1 specifically and potently blocked basal-to-apical transendothelia l 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-pr esenting dendritic cells (DC) migrate out of explants of cultured huma n skin and into the culture medium via dermal lymphatic-vessels, DC ad d T cells derived from skin expressed MDR-1 on their surfaces. Additio n 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%. I sotype-matched control mAbs against other DC molecules including CD18, CD31, and major histocompatibility complex I did not block. In the pr esence of MDR-1 antagonists, epidermal DC were retained in the epiderm is, in contrast to control conditions. In summary, this work identifie s a physiologic function for MDR-1 during the mobilization of DC and b egins to elucidate how these critical antigen-presenting cells migrate from the periphery to lymph nodes to initiate T lymphocyte-mediated i mmunity.