tacrolimus and herbimycin

Eosinophils are known to play an important role in the pathogenesis of asthma and other allergic diseases. This study demonstrated the effects of various drugs on eosinophil viability in vitro, which might help clinicians and researchers in treating and studying eosinophilic diseases. Staurosporine, a protein kinase C inhibitor, and herbimycin A, a tyrosine kinase inhibitor, at 10(-6) M and 10(-7) M significantly lowered eosinophil viability in a dose-dependent fashion (p < 0.002, p < 0.02 and p < 0.001, p < 0.002, respectively). Both staurosporine and herbimycin A reduced eosinophil survival in a time-dependent fashion at 10(-6) M and 10(-7) M. Ketotifen at 10(-4) M and theophylline at 10(-3) M, significantly decreased eosinophil viability (p < 0.001 and p < 0.001, respectively) in the presence of 100 pg/ml of recombinant human interleukin-5 (rhIL-5). Both FK506 and cyclosporin A at 10(-4) M significantly reduced eosinophil viability (p < 0.001 and p < 0.005, respectively) in the presence of 100 pg/ml of rhIL-5. Our data show that ketotifen, theophylline, FK506, cyclosporin A reduced eosinophil viability at a high concentration. Furthermore, it is suggested that protein kinase C and tyrosine kinase are involved in eosinophil survival.

Topics: Alkaloids; Asthma; Benzoquinones; Cell Survival; Cyclosporine; Eosinophils; Humans; Ketotifen; Lactams, Macrocyclic; Protein Kinase C; Protein-Tyrosine Kinases; Quinones; Rifabutin; Staurosporine; Tacrolimus; Theophylline

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.

Topics: Antibodies, Monoclonal; Benzoquinones; CD28 Antigens; Cells, Cultured; Cyclosporine; Drug Interactions; Humans; Immunosuppressive Agents; Interleukin-2; Lactams, Macrocyclic; Lymphocytes; Mycophenolic Acid; Polyenes; Quinones; Receptors, Antigen, T-Cell; Rifabutin; Sirolimus; Suramin; Tacrolimus