Biol. Chem. 2015; 396(6-7): 569–571
Guest Editorial
Highlight: Molecular Medicine of Sphingolipids DOI 10.1515/hsz-2015-0163
Ceramide is released from sphingomyelin by the activity of acid, neutral, and alkaline sphingomyelinases, is synthesized de novo, or both. Ceramide is converted to sphingosine by acid, neutral, or alkaline acid ceramidases; to ceramide-1-phosphate by ceramide kinase; and to glycosylated ceramide derivatives by glucosyltransferases. Sphingosine is further phosphorylated by sphingosine kinase (SPK) to sphingosine 1-phosphate (S1P), which is finally degraded by a lyase activity. Activation of acid sphingomyelinase (Asm) and a concomitant increase in the cellular ceramide concentration is triggered by diverse receptors including those for CD95, TNF, IL-1, and PAF, and by cellular stress such as ischemia, radiation, oxidative stress or chemotherapeutic agents (for a review see Grassmé et al., 2007). Ceramide seems to mainly act by changing biophysical properties of cellular membranes, thereby enabling redistribution of receptors and signaling molecules, conferring signal transduction driven by proximity (Grassmé et al., 2001). In contrast, S1P binds directly to a group of cell surface receptors, the S1P1-5 receptors, although it may also function as an intracellular message (Hla and Brinkmann, 2011; Maceyka et al., 2012). By cellular stimulation via these receptors, S1P regulates a multitude of cellular processes including proliferation and survival, angiogenesis, endothelial barrier function, cell mobility and chemotaxis, cytoskeleton organization, cellular calcium homeostasis, cell-tocell contact, adhesion, and recruitment of lymphocytes from lymph nodes into blood and sites of inflammation, an effect exploited clinically (Hla and Brinkmann, 2011; Maceyka et al., 2012). Signaling and biophysical aspects of ceramide and S1P in cells are highlighted in the articles by Carreira et al., Park et al., Deng et al., Prüfer et al. and Frohbergh et al. The present issue highlights some of the recent findings on the molecular medicine of sphingolipids, in particular the role of these lipids in cancer, infection, inflammation, organ regeneration, cardiovascular and neuropsychiatric diseases: Sphingolipids have been ascribed leading roles in the mechanism(s) of tumor cell death in response to ionizing radiation and various chemotherapies, and in the strategies that tumors adopt to avoid anti-cancer
therapy-induced death responses (Santana et al., 1996; Garcia-Barros et al., 2003; Lacour et al., 2004). These data established a role for Asm in host cells of the tumor microenvironment for the therapeutic response to radiation and to some chemotherapies. Furthermore, studies from several groups suggest that Asm signaling may not be restricted to a role in tumor stroma, as recent evidence indicates tumor cells, in some instances, may coincidentally signal effects of some chemotherapeutics in vivo via this pathway (Cheng et al., 2013). Kester et al., Hajj et al. and Czarnota describe the concepts of targeting and using sphingolipids in cancer and cancer treatment, respectively. The important role of the Asm/ceramide pathway in bacterial infection was first demonstrated for Neisseriae gonorrhoeae (Grassmé et al., 1997). These paradigmatic experiments were extended to studies of the role of the Asm/ceramide axis in infection with Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica serovar typhimurium, Mycobacterium avium, rhinovirus, measles virus, and Sindbis virus (for review see Becker et al., 2010). Hallmarks of infection, such as pathogen internalization, controlled release of cytokines, and induction of cell death, intracellular lysosome-phagosome fusion and maturation are mediated by the Asm/ceramide system. Very recent studies showed for the first time a major role of sphingosine in the innate, antibacterial defense of the lung against pathogens (Pewzner-Jung et al., 2014). The Asm/ceramide system is also important for regulation of inflammation. Signal transduction cascades induced by paradigmatic inflammatory cytokines such as IL-1β or TNF-α are initiated by Asm activation and ceramide release elicited by these cytokines (Schütze et al., 1992; Mathias et al., 1993). Acute lung injury induced by platelet-activating factor depends, at least in part, on activation of the Asm/ceramide pathway (Göggel et al., 2004). Increased ceramide concentrations play an important pathogenetic role in lungs of cystic fibrosis mice and patients (Teichgräber et al., 2008). These examples indicate the Asm/ceramide system may be fundamental in some types of inflammation, however mechanisms of its regulation and function remain, for the most part, unknown. The function of sphingolipids in inflammation
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
570 Guest Editorial are intimately related to their role in regeneration, a field in sphingolipid biology that only recently developed with very exciting novel concepts, for instance in liver regeneration. The role of sphingolipids in infectious biology, immunology and regeneration is presented in the contributions from Schneider Schaulies et al., Seitz et al., Vitner et al., Beyersdorf et al., Dillman et al. and Schröder et al., Jernigan et al., Hoehn et al. and Nojima et al. Sphingolipids are highly enriched in the cardiovascular system and play principal roles in development, physiology and pathology of this organ system. S1P and receptors control vascular development, vessel stability and crucial developmental events during embryonal morphogenesis and cardiogenesis (Mendelson et al., 2014). S1P is also an important player in inflammation and coagulation and controls inflammatory cell recruitment (Obinata and Hla, 2012). Hematopoietic stem cell trafficking from peripheral tissues into lymph and then into the vascular system is similarly regulated by S1P (Mandala et al., 2002). This effect of S1P requires expression of its S1P1 receptor on hematopoietic and immune cells. In 2010, the first functional antagonist of S1P receptors – Fingolimod (Gilenya®) – which potently inhibits trafficking of autoreactive immune cells into sites of inflammation was approved for the clinical treatment of relapsing multiple sclerosis (Suzuki et al., 1996). Finally, S1P signaling also regulates angiogenesis and other cancer-associated processes in the tumor microenvironment. Biomedical functions of S1P are discussed by Koch et al. and Schwalm et al. More recent findings demonstrated a crucial role of sphingolipids, in particular the Asm and ceramide in psychiatric disorders such as major depression. A highlight of major depressive disorder is a reduced neurogenesis in the hippocampus, a process that is regulated by the Asm and ceramide that serve as target for many antidepressants (Gulbins et al., 2013). The role of the sphingomyelinase in neuropsychiatric disorders is presently unknown and discussed in the article from Kornhuber et al., the role of S1P in nociception by Zhang et al. Thus, the past 25 years have completely changed our view of sphingolipids, which were previously considered to be primarily structural elements of cellular membranes. We now know that sphingolipids are central to many fundamental cellular processes. Very recent efforts translated these insights into clinical applications directed at treating, for example, multiple sclerosis, cancer, cystic fibrosis, pneumonia, major depression, neuro-degenerative diseases, or organ regeneration. The present issue
summarizes some of these efforts presented at the 2nd Conference on ‘Molecular Medicine of Sphingolipids’.
References Becker, K.A., Grassmé, H., Zhang, Y., and Gulbins, E. (2010). Ceramide in Pseudomonas aeruginosa infections and cystic fibrosis. Cell. Physiol. Biochem. 26, 57–66. Cheng, J.C., Bai, A., Beckham, T.H., Marrison, S.T., Yount, C.L., Young, K., Lu, P., Bartlett, A.M., Wu, B.X., Keane, B.J., et al. (2013). Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J. Clin. Invest. 123, 4344–4358. Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., and Kolesnick, R. (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159. Göggel, R., Winoto-Morbach, S., Vielhaber, G., Imai, Y., Lindner, K., Brade, L., Brade, H., Ehlers, S., Slutsky, A.S., Schutze, S., et al. (2004). PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat. Med. 10, 155–160. Grassmé, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., and Meyer, T.F. (1997). Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell 91, 605–615. Grassmé, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhof, K., Kolesnick, R., and Gulbins, E. (2001). CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596. Grassmé, H., Riethmüller, J., and Gulbins, E. (2007). Biological aspects of ceramide-enriched membrane domains. Prog. Lipid Res. 46, 161–170. Gulbins, E., Palmada, M., Reichel, M., Lüth, A., Böhmer, C., Amato, D., Müller, C.P., Tischbirek, C.H., Groemer, T.W., Tabatabai, G., et al. (2013). Acid sphingomyelinase/ceramide system mediates effects of antidepressant drugs. Nat. Med. 19, 934–938. Hla, T. and Brinkmann, V. (2011). Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology 76, S3–S8. Lacour, S., Hammann, A., Grazide, S., Lagadic-Gossmann, D., Athias, A., Sergent, O., Laurent, G., Gambert, P., Solary, E., and Dimanche-Boitrel, M.T. (2004). Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res. 64, 3593–3598. Maceyka, M., Harikumar, K.B., Milstien, S., and Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends Cell. Biol. 22, 50–60. Mandala, S., Hajdu, R., Bergstrom, J., Quackenbush, E., Xie, J., Milligan, J., Thornton, R., Shei, G.J., Card, D., Keohane, C., et al. (2002). Alteration of lymphocyte trafficking by sphingosine1-phosphate receptor agonists. Science 296, 346–349. Mathias, S., Younes, A., Kan, C.C., Orlow, I., Joseph, C., and Kolesnick, R.N. (1993). Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta. Science 259, 519–522. Mendelson, K., Evans, T., and Hla, T. (2014). Sphingosine 1-phosphate signalling. Development 141, 5–9.
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
Guest Editorial 571 Obinata, H. and Hla, T. (2012). Sphingosine 1-phosphate in coagulation and inflammation. Semin. Immunopathol. 34, 73–91. Pewzner-Jung, Y., Tavakoli Tabazavareh, S., Grassmé, H., Becker, K.A., Japtok, L., Steinmann, J., Joseph, T., Lang, S., Tuemmler, B., Schuchman, E.H., et al. (2014). Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa. EMBO Mol. Med. 6, 1205–1211. Santana, P., Pena, L.A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E.H., Fuks, Z., and Kolesnick, R. (1996). Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiationinduced apoptosis. Cell 86, 189–199. Schütze, S., Potthoff, K., Machleidt, T., Berkovic, D., Wiegmann, K., and Krönke, M. (1992). TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71, 765–776.
Teichgräber, V., Ulrich, M., Endlich, N., Riethmuller, J., Wilker, B., De Oliveira-Munding, C.C., van Heeckeren, A.M., Barr, M.L., von Kürthy, G., Schmid, K.W., et al. (2008). Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat. Med. 14, 382–391. Suzuki, S., Enosawa, S., Kakefuda, T., Shinomiya, T., Amari, M., Naoe, S., Hoshino, Y., and Chiba, K. (1996). A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation. Transplantation 6, 200–205. Erich Gulbins Molecular Biology University of Duisburg-Essen Germany e-mail: [email protected]
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
Guest Editorial
Highlight: Molecular Medicine of Sphingolipids DOI 10.1515/hsz-2015-0163
Ceramide is released from sphingomyelin by the activity of acid, neutral, and alkaline sphingomyelinases, is synthesized de novo, or both. Ceramide is converted to sphingosine by acid, neutral, or alkaline acid ceramidases; to ceramide-1-phosphate by ceramide kinase; and to glycosylated ceramide derivatives by glucosyltransferases. Sphingosine is further phosphorylated by sphingosine kinase (SPK) to sphingosine 1-phosphate (S1P), which is finally degraded by a lyase activity. Activation of acid sphingomyelinase (Asm) and a concomitant increase in the cellular ceramide concentration is triggered by diverse receptors including those for CD95, TNF, IL-1, and PAF, and by cellular stress such as ischemia, radiation, oxidative stress or chemotherapeutic agents (for a review see Grassmé et al., 2007). Ceramide seems to mainly act by changing biophysical properties of cellular membranes, thereby enabling redistribution of receptors and signaling molecules, conferring signal transduction driven by proximity (Grassmé et al., 2001). In contrast, S1P binds directly to a group of cell surface receptors, the S1P1-5 receptors, although it may also function as an intracellular message (Hla and Brinkmann, 2011; Maceyka et al., 2012). By cellular stimulation via these receptors, S1P regulates a multitude of cellular processes including proliferation and survival, angiogenesis, endothelial barrier function, cell mobility and chemotaxis, cytoskeleton organization, cellular calcium homeostasis, cell-tocell contact, adhesion, and recruitment of lymphocytes from lymph nodes into blood and sites of inflammation, an effect exploited clinically (Hla and Brinkmann, 2011; Maceyka et al., 2012). Signaling and biophysical aspects of ceramide and S1P in cells are highlighted in the articles by Carreira et al., Park et al., Deng et al., Prüfer et al. and Frohbergh et al. The present issue highlights some of the recent findings on the molecular medicine of sphingolipids, in particular the role of these lipids in cancer, infection, inflammation, organ regeneration, cardiovascular and neuropsychiatric diseases: Sphingolipids have been ascribed leading roles in the mechanism(s) of tumor cell death in response to ionizing radiation and various chemotherapies, and in the strategies that tumors adopt to avoid anti-cancer
therapy-induced death responses (Santana et al., 1996; Garcia-Barros et al., 2003; Lacour et al., 2004). These data established a role for Asm in host cells of the tumor microenvironment for the therapeutic response to radiation and to some chemotherapies. Furthermore, studies from several groups suggest that Asm signaling may not be restricted to a role in tumor stroma, as recent evidence indicates tumor cells, in some instances, may coincidentally signal effects of some chemotherapeutics in vivo via this pathway (Cheng et al., 2013). Kester et al., Hajj et al. and Czarnota describe the concepts of targeting and using sphingolipids in cancer and cancer treatment, respectively. The important role of the Asm/ceramide pathway in bacterial infection was first demonstrated for Neisseriae gonorrhoeae (Grassmé et al., 1997). These paradigmatic experiments were extended to studies of the role of the Asm/ceramide axis in infection with Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, Salmonella enterica serovar typhimurium, Mycobacterium avium, rhinovirus, measles virus, and Sindbis virus (for review see Becker et al., 2010). Hallmarks of infection, such as pathogen internalization, controlled release of cytokines, and induction of cell death, intracellular lysosome-phagosome fusion and maturation are mediated by the Asm/ceramide system. Very recent studies showed for the first time a major role of sphingosine in the innate, antibacterial defense of the lung against pathogens (Pewzner-Jung et al., 2014). The Asm/ceramide system is also important for regulation of inflammation. Signal transduction cascades induced by paradigmatic inflammatory cytokines such as IL-1β or TNF-α are initiated by Asm activation and ceramide release elicited by these cytokines (Schütze et al., 1992; Mathias et al., 1993). Acute lung injury induced by platelet-activating factor depends, at least in part, on activation of the Asm/ceramide pathway (Göggel et al., 2004). Increased ceramide concentrations play an important pathogenetic role in lungs of cystic fibrosis mice and patients (Teichgräber et al., 2008). These examples indicate the Asm/ceramide system may be fundamental in some types of inflammation, however mechanisms of its regulation and function remain, for the most part, unknown. The function of sphingolipids in inflammation
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
570 Guest Editorial are intimately related to their role in regeneration, a field in sphingolipid biology that only recently developed with very exciting novel concepts, for instance in liver regeneration. The role of sphingolipids in infectious biology, immunology and regeneration is presented in the contributions from Schneider Schaulies et al., Seitz et al., Vitner et al., Beyersdorf et al., Dillman et al. and Schröder et al., Jernigan et al., Hoehn et al. and Nojima et al. Sphingolipids are highly enriched in the cardiovascular system and play principal roles in development, physiology and pathology of this organ system. S1P and receptors control vascular development, vessel stability and crucial developmental events during embryonal morphogenesis and cardiogenesis (Mendelson et al., 2014). S1P is also an important player in inflammation and coagulation and controls inflammatory cell recruitment (Obinata and Hla, 2012). Hematopoietic stem cell trafficking from peripheral tissues into lymph and then into the vascular system is similarly regulated by S1P (Mandala et al., 2002). This effect of S1P requires expression of its S1P1 receptor on hematopoietic and immune cells. In 2010, the first functional antagonist of S1P receptors – Fingolimod (Gilenya®) – which potently inhibits trafficking of autoreactive immune cells into sites of inflammation was approved for the clinical treatment of relapsing multiple sclerosis (Suzuki et al., 1996). Finally, S1P signaling also regulates angiogenesis and other cancer-associated processes in the tumor microenvironment. Biomedical functions of S1P are discussed by Koch et al. and Schwalm et al. More recent findings demonstrated a crucial role of sphingolipids, in particular the Asm and ceramide in psychiatric disorders such as major depression. A highlight of major depressive disorder is a reduced neurogenesis in the hippocampus, a process that is regulated by the Asm and ceramide that serve as target for many antidepressants (Gulbins et al., 2013). The role of the sphingomyelinase in neuropsychiatric disorders is presently unknown and discussed in the article from Kornhuber et al., the role of S1P in nociception by Zhang et al. Thus, the past 25 years have completely changed our view of sphingolipids, which were previously considered to be primarily structural elements of cellular membranes. We now know that sphingolipids are central to many fundamental cellular processes. Very recent efforts translated these insights into clinical applications directed at treating, for example, multiple sclerosis, cancer, cystic fibrosis, pneumonia, major depression, neuro-degenerative diseases, or organ regeneration. The present issue
summarizes some of these efforts presented at the 2nd Conference on ‘Molecular Medicine of Sphingolipids’.
References Becker, K.A., Grassmé, H., Zhang, Y., and Gulbins, E. (2010). Ceramide in Pseudomonas aeruginosa infections and cystic fibrosis. Cell. Physiol. Biochem. 26, 57–66. Cheng, J.C., Bai, A., Beckham, T.H., Marrison, S.T., Yount, C.L., Young, K., Lu, P., Bartlett, A.M., Wu, B.X., Keane, B.J., et al. (2013). Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse. J. Clin. Invest. 123, 4344–4358. Garcia-Barros, M., Paris, F., Cordon-Cardo, C., Lyden, D., Rafii, S., Haimovitz-Friedman, A., Fuks, Z., and Kolesnick, R. (2003). Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300, 1155–1159. Göggel, R., Winoto-Morbach, S., Vielhaber, G., Imai, Y., Lindner, K., Brade, L., Brade, H., Ehlers, S., Slutsky, A.S., Schutze, S., et al. (2004). PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat. Med. 10, 155–160. Grassmé, H., Gulbins, E., Brenner, B., Ferlinz, K., Sandhoff, K., Harzer, K., Lang, F., and Meyer, T.F. (1997). Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell 91, 605–615. Grassmé, H., Jekle, A., Riehle, A., Schwarz, H., Berger, J., Sandhof, K., Kolesnick, R., and Gulbins, E. (2001). CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596. Grassmé, H., Riethmüller, J., and Gulbins, E. (2007). Biological aspects of ceramide-enriched membrane domains. Prog. Lipid Res. 46, 161–170. Gulbins, E., Palmada, M., Reichel, M., Lüth, A., Böhmer, C., Amato, D., Müller, C.P., Tischbirek, C.H., Groemer, T.W., Tabatabai, G., et al. (2013). Acid sphingomyelinase/ceramide system mediates effects of antidepressant drugs. Nat. Med. 19, 934–938. Hla, T. and Brinkmann, V. (2011). Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology 76, S3–S8. Lacour, S., Hammann, A., Grazide, S., Lagadic-Gossmann, D., Athias, A., Sergent, O., Laurent, G., Gambert, P., Solary, E., and Dimanche-Boitrel, M.T. (2004). Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res. 64, 3593–3598. Maceyka, M., Harikumar, K.B., Milstien, S., and Spiegel, S. (2012). Sphingosine-1-phosphate signaling and its role in disease. Trends Cell. Biol. 22, 50–60. Mandala, S., Hajdu, R., Bergstrom, J., Quackenbush, E., Xie, J., Milligan, J., Thornton, R., Shei, G.J., Card, D., Keohane, C., et al. (2002). Alteration of lymphocyte trafficking by sphingosine1-phosphate receptor agonists. Science 296, 346–349. Mathias, S., Younes, A., Kan, C.C., Orlow, I., Joseph, C., and Kolesnick, R.N. (1993). Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1 beta. Science 259, 519–522. Mendelson, K., Evans, T., and Hla, T. (2014). Sphingosine 1-phosphate signalling. Development 141, 5–9.
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
Guest Editorial 571 Obinata, H. and Hla, T. (2012). Sphingosine 1-phosphate in coagulation and inflammation. Semin. Immunopathol. 34, 73–91. Pewzner-Jung, Y., Tavakoli Tabazavareh, S., Grassmé, H., Becker, K.A., Japtok, L., Steinmann, J., Joseph, T., Lang, S., Tuemmler, B., Schuchman, E.H., et al. (2014). Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa. EMBO Mol. Med. 6, 1205–1211. Santana, P., Pena, L.A., Haimovitz-Friedman, A., Martin, S., Green, D., McLoughlin, M., Cordon-Cardo, C., Schuchman, E.H., Fuks, Z., and Kolesnick, R. (1996). Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiationinduced apoptosis. Cell 86, 189–199. Schütze, S., Potthoff, K., Machleidt, T., Berkovic, D., Wiegmann, K., and Krönke, M. (1992). TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced “acidic” sphingomyelin breakdown. Cell 71, 765–776.
Teichgräber, V., Ulrich, M., Endlich, N., Riethmuller, J., Wilker, B., De Oliveira-Munding, C.C., van Heeckeren, A.M., Barr, M.L., von Kürthy, G., Schmid, K.W., et al. (2008). Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat. Med. 14, 382–391. Suzuki, S., Enosawa, S., Kakefuda, T., Shinomiya, T., Amari, M., Naoe, S., Hoshino, Y., and Chiba, K. (1996). A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation. Transplantation 6, 200–205. Erich Gulbins Molecular Biology University of Duisburg-Essen Germany e-mail: [email protected]
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 6/17/15 3:30 AM
