The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro.
ISA247 is a novel cyclosporine analog. In this study we compare, in vitro, the effects of ISA247 on immune function with those of cyclosporine. Whole blood from cynomolgus monkeys (n = 5) was incubated with different concentrations of ISA247 or cyclosporine and stimulated with different mitogens in culture medium. Lymphocyte proliferation was assessed by [3H]-TdR incorporation assay and by flow cytometry. Flow cytometry was also used to assess production of intracellular cytokines by T cells and expression of T cell activation surface antigens. The concentration of drug necessary to attain 50% of the maximum effect (EC50) was subsequently calculated. EC50 values for ISA247 were lower than for cyclosporine, and the differences were statistically significant for lymphocyte proliferation, T cell cytokine production, and expression of all T cell activation surface antigens but one. We conclude that ISA247 suppresses diverse immune functions more potently than cyclosporine in vitro.
Bîrsan
Tudor
T
Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, USA.
Dambrin
Camille
C
Freitag
Derrick G
DG
Yatscoff
Randall W
RW
Morris
Randall E
RE
D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008252:Macaca fascicularis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C484071:voclosporin; D007371:Interferon-gamma; D016572:Cyclosporine; D019703:Calcineurin