FTY720 is a novel immunomodulator that has proven effective in animal models of transplantation and autoimmunity, has achieved promising results in Phase I and Phase II studies of renal transplantation in humans, and is currently undergoing phase III studies. FTY720 acts as a high-affinity agonist at the sphingosine 1-phosphate receptor-1 (S1P1), where it internalises the receptor and causes alterations to the normal circulation of lymphocytes between the blood and lymphoid tissue. Unlike conventional immunosuppressants, FTY720 does not impair the activation, proliferation or effector functions of T- and B-cells. Further development of FTY720 is in progress, including trials in autoimmune disorders as well as transplantation. This review summarises the mechanism of action of FTY720, its effects in models of transplantation and autoimmunity, and results from clinical trials in humans.
Animals ; Autoimmune Diseases/drug therapy ; Clinical Trials ; Endothelium, Vascular/drug effects ; Humans ; Immune System/drug effects ; Immunosuppressive Agents/*therapeutic use ; *Organ Transplantation ; Propylene Glycols/*therapeutic use ; Receptors, Lysosphingolipid/agonists ; Transplantation Immunology

Sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions in both intracellular and extracellular compartments. It interacts with five G protein-coupled receptors subtypes (S1PR(1-5)) to generate multiple downstream signaling. Activation of S1PR1 has been validated to be involved in the process of immune modulation. Fingolimod (FTY720), the novel S1PR1 agonist, has been approved for the treatment of multiple sclerosis in clinical trials. The study towards discovery of selective S1PR1 agonists has become hot spot for immunological diseases. This article summarized the research progress of S1PR1 agonists, emphasizing their structure types, structure-activity relationship and direction of development.
Animals ; Fingolimod Hydrochloride ; Humans ; Immunosuppressive Agents ; pharmacology ; therapeutic use ; Lysophospholipids ; physiology ; Multiple Sclerosis ; drug therapy ; Propylene Glycols ; pharmacology ; therapeutic use ; Receptors, Lysosphingolipid ; agonists ; classification ; metabolism ; physiology ; Sphingosine ; analogs & derivatives ; pharmacology ; physiology ; therapeutic use ; Structure-Activity Relationship

Syl948 is a synthesized selective S1P1 agonist with novel structure. HTRF-IP1 test indicated that Syl948-P, the active form of Syl948 in vitro, has strong activity against S1P1 (EC50: 83 +/- 16 nmol x L(-1)), but its effect on S1P3 was very weak (EC50: 1 026 +/- 90 nmol x L(-1)). In SD rats, oral administration of Syl948 10 mg x kg(-1) significantly decreased the peripheral blood lymphocytes (PBL), with the maximal PBL inhibition rate of 63%, which was as similar as equal dose of fingolimod (FTY720). Oral administration of Syl948 10 mg x kg(-1) had no effect on heart rate of SD rats, which was better than FTY720. Daily oral administration with Syl948 (2 or 4 mg x kg(-1)) significantly prolonged the survival time of the allografts of skin slice on mice. In summary, the above results demonstrated that Syl948 has great selectivity in vitro and good activity in vivo, which indicated its potential use as an anti-rejection drug in skin transplantation.
Animals ; Fingolimod Hydrochloride ; Graft Survival ; drug effects ; Immunosuppressive Agents ; pharmacology ; Lymphocytes ; drug effects ; Mice ; Propylene Glycols ; pharmacology ; Rats ; Receptors, Lysosphingolipid ; agonists ; Skin Transplantation ; Sphingosine ; analogs & derivatives ; pharmacology ; Transplantation, Homologous

FTY720 is a synthetic compound derived from the metabolites of Isaria sinclairii. Its unique chemical structure and mechanism appear to be distinctive from other known immunosuppressors. In the present study, the effect of FTY720 on immunosuppression and toxicity to heart was evaluated by detection of lymphocytes count, heart rate in rats, the survival time of the allografts of skin slice in mice and binding to S1P1 and S1P3 receptors by confocal. The results showed that FTY720 could induce lymphopenia, reduce the heart rates in rats and prolong the survival time of the allografts of skin slice in mice. The assay results on confocal showed that FTY720 can bind with S1P1 and S1P3 on surface of CHO-S1P1 and CHO-S1P3 cells. FTY720 could be developed for wide application for organ transplantation and self-immunity diseases.
Animals ; Cricetinae ; Cricetulus ; Female ; Fingolimod Hydrochloride ; Graft Survival ; drug effects ; Heart Rate ; drug effects ; Immunosuppressive Agents ; pharmacology ; Lymphocyte Count ; Lymphocytes ; cytology ; drug effects ; Lymphopenia ; chemically induced ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Microscopy, Confocal ; Propylene Glycols ; pharmacology ; Protein Binding ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Lysosphingolipid ; agonists ; metabolism ; Skin Transplantation ; Sphingosine ; analogs & derivatives ; pharmacology ; Transplantation, Homologous