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Specific MDR1 P-Glycoprotein Blockade Inhibits Human Alloimmune T Cell Activation In Vitro¹

Markus H. Frank^*,, Mark D. Denton^*,, Stephen I. Alexander, Samia J. Khoury, Mohamed H. Sayegh^2, and David M. Briscoe^2,3,*

^* Division of Nephrology, Children’s Hospital, Harvard Medical School, Boston, MA 02115; Laboratory of Immunogenetics and Transplantation, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115; and Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

MDR1 P-glycoprotein (P-gp), the multidrug resistance-associated transmembrane transporter, is physiologically expressed by human peripheral immune cells, but its role in cell-mediated immunity remains poorly understood. Here, we demonstrate a novel role for P-gp in alloantigen-dependent human T cell activation. The pharmacologic P-gp inhibitor tamoxifen (1–10 µM) and the MDR1 P-gp-specific mAb Hyb-241 (1–20 µg/ml), which detected surface P-gp on 21% of human CD3⁺ T cells and 84% of CD14⁺ APCs in our studies, inhibited alloantigen-dependent, but not mitogen-dependent, T cell proliferation in a dose-dependent manner from 40–90% (p < 0.01). The specific inhibitory effect on alloimmune T cell activation was associated with >85% inhibition (p < 0.01) of IL-2, IFN-, and TNF- production in 48-h MLR coculture supernatants. Addition of recombinant human IL-2 (0.1–10 ng/ml) restored proliferation in tamoxifen-treated cocultures. Pretreatment of purified CD4⁺ T cells with Hyb-241 mAb before coculture resulted in inhibition of CD4⁺ T cellular IFN- secretion. Also, blockade of P-gp on allogeneic APCs inhibited IL-12 secretion. Taken together these results demonstrate that P-gp is functional on both CD4⁺ T cells and CD14⁺ APCs, and that P-gp blockade may attenuate both IFN- and IL-12 through a positive feedback loop. Our results define a novel role for P-gp in alloimmunity and thus raise the intriguing possibility that P-gp may represent a novel therapeutic target in allograft rejection.

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