ENHANCING THE EFFECT OF SECRETED CYCLOPHILIN-B ON IMMUNOSUPPRESSIVE ACTIVITY OF CYCLOSPORINE

Background. Cyclophilin B (CyPB) is a cyclosporine (CsA)-binding prote in, located within intracellular vesicles and secreted in biological f luids. In previous works, we reported that CyPB specifically interacts with the T-cell membrane and potentiates the ability of CsA to inhibi t CD3-induced proliferation of T lymphocytes. Methods. CyPB levels wer e measured in plasma from healthy donors and transplant patients. The role of extracellular CyPB on the distribution and activity of CsA was investigated first by studies on the uptake of free and CyPB-complexe d drug by blood cells, and second by studies on the inhibitory effects of these two compounds on the CD3-induced proliferation of peripheral blood mononuclear cells. Results. A significant increase in plasma Cy PB level was observed for CsA-treated patients (13+/-6.4 nM, n=42) in comparison with untreated donors (4.3+/-2.1 nM, n=34). In vitro, extra cellular CyPB dose dependently modified CsA distribution between plasm a, erythrocyte, and lymphocyte contents, by both retaining the complex ed drug extracellularly and promoting its specific accumulation within peripheral blood mononuclear cells. Moreover, the enhanced ability of CyPB-complexed CsA to suppress CD3-induced T-cell proliferation was p reserved in the presence of other blood cells, implying specific targe ting of the drug to sensitive cells. Furthermore, although a large int erindividual variability of sensitivity to the drug was confirmed for 18 individuals, we found that CyPB potentiated the activity of CsA in restoring a high sensitivity to the immunosuppressant. Conclusion. The se results suggest that plasma CyPB may contribute to the acceptance a nd the good maintenance of organ transplantation by enhancing the immu nosuppressive activity of CsA through a receptor-mediated incorporatio n of CyPB-complexed CsA within peripheral blood lymphocytes.