The interaction of immunosuppressive compounds in tandem stimulated peripheral human lymphocytes.
We have developed an in vitro system to model the interactions of drugs used to treat transplant rejection. This system consists of stimulation of human lymphocytes with a primary mitogen (anti-T-cell receptor complex antibodies (OKT3 or wt31)) and treatment with a primary immunosuppressive drug (ISD) (Cyclosporine A (CsA) or FK-506)). This is later followed by stimulation with a secondary mitogen (Interleukin-2 or anti-CD28), and treatment with a second ISD. This system allows a variety of concentrations and compounds to be rapidly tested. We have used this system to study the effect of various compounds when used as either primary or secondary ISDs. Our results show that when CsA is used as the primary ISD, further proliferation can be inhibited by rapamycin, mycophenolic acid, or suramin. When FK-506 is the primary ISD, inhibition of proliferation by rapamycin is variable depending on the primary and secondary mitogens. If rapamycin is the primary ISD, both CsA and FK-506 show antagonistic interactions. These results suggest that the order in which combinations of ISDs are administered in transplantation may have significant effects on the clinical outcome.
Weaver
J L
JL
Division of Research and Testing, Food and Drug Administration, Washington, DC 20204.
Pine
P S
PS
Aszalos
A
A
D000911:Antibodies, Monoclonal / Q000276:immunology; D016227:Benzoquinones; D018106:CD28 Antigens / Q000276:immunology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology; D047029:Lactams, Macrocyclic; D008214:Lymphocytes / Q000187:drug effects*; D009173:Mycophenolic Acid / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017828:Rifabutin / Q000031:analogs & derivatives; D020123:Sirolimus; D013498:Suramin / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D018106:CD28 Antigens; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D047029:Lactams, Macrocyclic; D011090:Polyenes; D011809:Quinones; D011948:Receptors, Antigen, T-Cell; D017828:Rifabutin; D013498:Suramin; C020754:herbimycin; D016572:Cyclosporine; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus