RESUMEN
BACKGROUND: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. METHODS AND RESULTS: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. CONCLUSIONS: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Trasplante de Piel/inmunología , Compuestos de Sulfhidrilo/uso terapéutico , Animales , Bradicardia/prevención & control , Quimiotaxis de Leucocito/efectos de los fármacos , Enfermedad Crónica , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Evaluación Preclínica de Medicamentos , Quimioterapia Combinada , Clorhidrato de Fingolimod , Rechazo de Injerto/prevención & control , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Inmunosupresores/química , Inmunosupresores/farmacología , Masculino , Estructura Molecular , Glicoles de Propileno/farmacología , Glicoles de Propileno/uso terapéutico , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Endogámicas , Ratas Wistar , Esfingosina/análogos & derivados , Compuestos de Sulfhidrilo/administración & dosificación , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/farmacología , Trasplante Heterotópico , Trasplante Homólogo/inmunologíaRESUMEN
Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the treatment of rat experimental autoimmune myocarditis. KRP-203 significantly attenuated the inflammation area, heart weight/body weight ratio, and left ventricular function. Immunohistochemical analysis and RT-PCR revealed that KRP-203 significantly decreased the infiltration of macrophages and CD4 T cells in the myocardium and the expression of inflammatory cytokines. Flow cytometric analysis revealed that treatment with KRP-203 effectively reduced the number of peripheral CD4 and CD8 T cells but not that of B cells and granulocytes. Further, late KRP-203 treatment was effective even against established EAM. These results demonstrate the therapeutic potential of KRP-203 for the treatment of human myocarditis and provide new insights into the pathogenesis of this disease.