Abstract
Exposure of cytolytically susceptible human target cells with therapeutic concentrations of the immunosuppressive drug cyclosporin A renders these cells highly resistant to T cell-mediated, natural killer (NK) cell-mediated, and complement-mediated cytolysis. The resistance is dose dependent, time dependent and reversible. The resistance is accompanied by target cell growth inhibition as measured by thymidine uptake. Surprisingly, target cell growth inhibition induced by serum depletion is associated with cell-mediated cytolytic resistance. These data suggest that cyclosporin A (CsA) may block some target cell biochemical pathway(s) important in the suicidal cytolytic process which is (are) linked to some G0/G1 cell cycle events. In addition, these results suggest that the increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in human organ transplant recipients may be contributed to by CsA-induced resistance of EBV-transformed B lymphocytes to immune cytolysis. In the post-transplant setting, CsA probably blocks T cell-dependent responses to EBV-transformed B lymphocytes (Bird, A.G., McLachlan, S.M. and Britton, S., Nature 1981, 289: 300) yet leaving the NK cell and antibody-dependent responses intact (Shao-Hsien, C. et al. Transplantation 1983. 35: 127). However, given the direct effect of CsA upon EBV-transformed B lymphocytes, these cells would be rendered resistant to nearly all forms of cytolytic immune control (cytotoxic T lymphocyte, natural killer, antibody-dependent cell-mediated cytotoxicity, complement). Unregulated EBV-transformed B lymphocytes may then proliferate in the CsA-treated host thus leading to a polyclonal B cell hyperplasia. Our data would suggest that this early pre-malignant process is likely to be reversible following CsA dose reduction. Indeed, EBV-dependent polyclonal B cell hyperplasia is seen in early post-transplant lymphoproliferative disorders (Hanto, D.W., et al., Transplantation 1989, 47: 458). Furthermore, in some cases CsA dose reduction does lead to disease regression (Starzl, T., et al., Lancet 1984. i: 583). However, further progression of the disease probably occurs following chromosomal changes leading to oncogene activation and might be resistant to CsA dose reduction.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.