Comparative assessment of transient exposure of paclitaxel or zotarolimus on in vitro vascular cell death, proliferation, migration, and proinflammatory biomarker expression.

Both paclitaxel and zotarolimus are currently employed in vascular interventional therapies, such as drug-eluting stents, and are under investigation for use in other novel drug-device combination products. Paclitaxel is a microtubule-stabilizing compound with potent antiproliferative properties and antimigration effects, whereas zotarolimus is a potent mammalian target of rapamycin inhibitor with antiproliferative and antiinflammatory properties. This study was intended to compare paclitaxel and zotarolimus for intravascular applications in which drug exposure time may be reduced, such as in drug-coated balloons. These applications are generally aimed at reducing neointimal hyperplasia by limiting smooth muscle cell (SMC) proliferation and inflammatory cell recruitment, while minimally interfering with vessel reendothelialization after balloon denudation. In the cellular models described in this study, transient exposure of zotarolimus resulted in the sustained inhibition of SMC proliferation and reduced endothelial cell (EC) proinflammatory cytokine expression, while not affecting EC migration and viability. Transient exposure of paclitaxel inhibited SMC proliferation, EC migration, and overall cell viability, with no effect on expression of the proinflammatory biomarkers studied.

Cardiac allografts from IL-4 knockout recipients: assessment of transplant arteriosclerosis and peripheral tolerance.

To study the role of IL-4 in tolerance induction and transplant arteriosclerosis, BALB/c hearts were transplanted into C57BL/6J wild-type or IL-4 knockout (IL-4(-/-)) recipients. A 30-day course of anti-CD4/8 mAb was used to induce long term graft survival. Primary graft survival was 50% (5 of 10) in IL-4(-/-) recipients comparable to 63% (5 of 8) in wild-type recipients. Mice with allografts surviving >80 days were tested for tolerance by challenge with a second donor or third party (CBA) heart. Secondary donor-strain heart grafts survived >30 days, but showed histologic evidence of ongoing alloimmune response. Third party hearts rejected rapidly. Although immunostaining and 32P RT-PCR assays showed no differences in the mononuclear cell infiltration and T cell activation between IL-4(-/-) and wild-type tolerant recipients, some monokines (IL-12, TNF-alpha, and allograft inflammatory factor-1) were up-regulated in grafts from IL-4(-/-) recipients. Computer-assisted analysis of elastin-stained vessels revealed that the severity of vascular thickening (percentage of luminal occlusion, mean +/- SD, n = 329) was similar in grafts from IL-4(-/-) (63.7 +/- 16.9%) and wild-type (69.5 +/- 17.6%) recipients. Thus, IL-4 deficiency did not alter primary or secondary graft survival, infiltration, or vascular thickening. The selective alterations in monokine expression suggests that alternative pathways are activated and may compensate in IL-4(-/-) mice.