P-glycoprotein - A Novel Therapeutic Target for Immunomodulation in Clinical Transplantation and Autoimmunity?

S.      Pendse; H.   M.   Sayegh; H.   M.   Frank

Abstract

P-glycoprotein, the human MDR1 gene product and cancer multidrug resistance-associated ATP-binding cassette transporter, is physiologically expressed on peripheral blood mononuclear cells, but its role in cellular immunity is only beginning to be elucidated. A role of P-glycoprotein in the secretion of several T cell- and antigen presenting cellderived cytokines has been described, and additional functions of the molecule have been identified in lymphocyte survival and antigen presenting cell differentiation. Taken together, these findings provide compelling evidence that Pglycoprotein serves several distinct functions in the initiation of primary immune responses, and a critical role of the molecule in functional immune responses is now established. Here, we will review the current understanding of Pglycoprotein function in T cell activation and antigen presenting cell function, which are relevant to the fields of clinical transplantation and autoimmunity, and summarize the evidence for in vitro and in vivo immunomodulatory actions of several known P-glycoprotein-inhibiting agents currently in clinical use for other indications. We suggest that it is the Pglycoprotein- inhibitory function of many of these agents that underly their immunoregulatory capacities. Thus, the established immunoregulatory function of P-glycoprotein and the availability of P-glycoprotein-inhibitory drugs raise the possibility that P-glycoprotein may represent a promising novel therapeutic target for immune modulation in acute and chronic allograft rejection, and cell-mediated autoimmune disorders.

Keywords: p-glycoprotein, t cells, dendritic cells, natural killer cells, immunosuppression, psc833, tamoxifen, alloimmunity