Immunosuppressive therapy in organ transplant patients is complicated by many factors that are incompletely understood. One factor that is emerging as a critical component of drug effect is the interaction of a membrane pump called p- glycoprotein (P-gp) with a number of drugs administered to organ transplant patients. Of particular importance is the interaction between P-gp and cyclosporine (CsA). The P-gp pump may restrict the access of CsA to the cell, or CsA may inhibit pump function and allow other pump substrates to enter the cell. P- glycoprotein also is involved in cytokine secretion in T lymphocytes. Blockade of cytokine secretion is an additional mechanism of action of CsA that may be in effect when the drug is present in very high concentrations. A new clinical protocol which is unique to our center examines the administration of CsA by aerosol to lung transplant patients. This NIH-sponsored (R01) trial will examine the use of CsA aerosol as prophylaxis of lung transplant rejection in a double-blinded fashion. We propose to use cells obtained from the bronchoalveolar lavage (BAL) of lung transplant patients in this trial to examine several critical factors related to P-gp function and response.
Our specific aims are to (1) examine P-gp function in T cells isolated from BAL in comparision to peripheral blood T cells in aerosol-treated verses placebo-treated lung transplant patients, (2) determine the effect of aerosolized CsA on P-gp-mediated cytokine secretion, and (3) determine the effect of chronic aerosol CsA therapy on the modulation of P-gp activity in T cells from BAL and peripheral blood. The primary method of assessment of P-gp activity will be multiparameter flow cytometry. Having a closely-monitored patient population, a double-blinded protocol for the administration of high concentrations of CsA directly into the allograft, and the collaboration of an experienced team of investigators with backgrounds in pharmacology, immunology, flow cytometry and transplantation combine to provide a unique opportunity to assess the role of P-gp in immunosuppressive therapy.
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