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HIS Supplement of Transplantation Proceedings contains articles describing a recent advance in clinical therapy—the introduction of inhibitors of mammalian Target of Rapamycin (mTOR). This serine-threonine kinase mediates the cellular responses to be a broad array of cytokine humoral mediators. mTOR enzymatic action is critical for cell cycle progression through the G1 phase, interrupting both pathways of protein synthesis and generation of transcription factors. Therefore inhibition of this compelling target disrupts a broad range of physiologic processes. The blockade of mTOR interrupts adaptive T and B cell responses that mediate recognition and destruction of foreign tissues. When used as a base therapy, blockade of mTOR is about equal to that engendered by calcineurin antagonists. When used in combination with even modest doses of cyclosporine, the profound degree of synergistic interactions markedly reduces the occurrence of acute graft rejection episodes and forestalls chronic nephropathic processes. Furthermore, purine nucleoside synthesis blockers show favorable effects when administered with mTOR inhibitors. Thus the experience of the authors as described herein show that application of this strategy yields further advances in the transplantation of renal, pancreatic, cardiac and hepatic grafts. However, as is to be predicted by the multifaceted actions of mTOR, administration of inhibitors of this enzyme is associated with a pleiotropic array of side effects, as detailed by the contributions in this Volume. Since it has been
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 000 (2003)
only three years since approval of the mTOR strategy by the Food and Drug Administration, these reactions are not completely understood. At present, it appears that at least the most frequent toxicities—altered lipid metabolism and myelosuppression— correlate with the mechanism of action. While follow-up studies suggest that these responses seem to ameliorate over time, their overall impact will only be discerned with longer periods of observation. The thrust of this Volume is the multiple descriptions of various approaches by different clinicians to employ mTOR inhibition in the settings of induction therapy, acute rejection prophylaxis and maintenance immunosuppression. The optimal therapeutic strategy for this innovative enterprise is presently unclear. Future linkage of meticulous clinical observations with pharmacokinetic and pharmacodynamic surrogates will doubtless enhance our understanding of the role of the mTOR inhibitors within the matrix of clinical immunosuppressants. I with to thank all the contributors for their participation in this Volume, and particularly Gailen D. Marshall, Jr. MD, PhD, Chair, Continuing Medical Education Advisory Committee—The University of Texas Medical School at Houston and the Office of Continuing Medical Education at the University of Texas Medical School at Houston for his assistance in bringing this Continuing Medical Education activity to fruition. Barry D. Kahan, PhD, MD Guest Editor
0041-1345/03/$–see front matter doi:10.1016/S0000-0000(03)00000-0 ix
T
HIS Supplement of Transplantation Proceedings contains articles describing a recent advance in clinical therapy—the introduction of inhibitors of mammalian Target of Rapamycin (mTOR). This serine-threonine kinase mediates the cellular responses to be a broad array of cytokine humoral mediators. mTOR enzymatic action is critical for cell cycle progression through the G1 phase, interrupting both pathways of protein synthesis and generation of transcription factors. Therefore inhibition of this compelling target disrupts a broad range of physiologic processes. The blockade of mTOR interrupts adaptive T and B cell responses that mediate recognition and destruction of foreign tissues. When used as a base therapy, blockade of mTOR is about equal to that engendered by calcineurin antagonists. When used in combination with even modest doses of cyclosporine, the profound degree of synergistic interactions markedly reduces the occurrence of acute graft rejection episodes and forestalls chronic nephropathic processes. Furthermore, purine nucleoside synthesis blockers show favorable effects when administered with mTOR inhibitors. Thus the experience of the authors as described herein show that application of this strategy yields further advances in the transplantation of renal, pancreatic, cardiac and hepatic grafts. However, as is to be predicted by the multifaceted actions of mTOR, administration of inhibitors of this enzyme is associated with a pleiotropic array of side effects, as detailed by the contributions in this Volume. Since it has been
© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 000 (2003)
only three years since approval of the mTOR strategy by the Food and Drug Administration, these reactions are not completely understood. At present, it appears that at least the most frequent toxicities—altered lipid metabolism and myelosuppression— correlate with the mechanism of action. While follow-up studies suggest that these responses seem to ameliorate over time, their overall impact will only be discerned with longer periods of observation. The thrust of this Volume is the multiple descriptions of various approaches by different clinicians to employ mTOR inhibition in the settings of induction therapy, acute rejection prophylaxis and maintenance immunosuppression. The optimal therapeutic strategy for this innovative enterprise is presently unclear. Future linkage of meticulous clinical observations with pharmacokinetic and pharmacodynamic surrogates will doubtless enhance our understanding of the role of the mTOR inhibitors within the matrix of clinical immunosuppressants. I with to thank all the contributors for their participation in this Volume, and particularly Gailen D. Marshall, Jr. MD, PhD, Chair, Continuing Medical Education Advisory Committee—The University of Texas Medical School at Houston and the Office of Continuing Medical Education at the University of Texas Medical School at Houston for his assistance in bringing this Continuing Medical Education activity to fruition. Barry D. Kahan, PhD, MD Guest Editor
0041-1345/03/$–see front matter doi:10.1016/S0000-0000(03)00000-0 ix