Novel mode of action of the calcium antagonist mibefradil (Ro 40-5967): potent immunosuppression by inhibition of T-cell infiltration through allogeneic endothelium.
Cyclosporin A reduces the mitotic activity of allosensitized lymphocytes, but fails to limit emigration of these cells into the donor organ. However, the modulation of both lymphocyte proliferation and infiltration are desirable characteristics of immunosuppressive therapy. The calcium-channel blocker, verapamil, has recently been shown to effectively prevent the transmigration of CD4+ and CD8+ T cells through allogeneic endothelium. Mibefradil (Ro 40-5967) represents a new generation of calcium antagonists with high potency and long-term activity. To evaluate the immunosuppressive potential of this drug, the influence of mibefradil on lymphocyte adhesion to, horizontal locomotion along, and penetration through allogeneic endothelium (HUVEC) was performed. When lymphocytes were prestimulated for 24 hr with mibefradil, adhesion and penetration were dose-dependently reduced. The adhesion ID50 values were 3.4 microM (CD4+ T cells) versus 9.2 microM (CD8+ T cells) and 2.1 microM (CD4+ T cells) versus 3.9 microM (CD8+ T cells) with regard to penetration. Mibefradil also effectively blocked horizontal locomotion. Specific down-regulation of T-cell binding to the P-selection receptor (ID50: CD4+ T cells, 0.8 microM: CD8+ T cells, 1.2 microM) and to the intracellular adhesion molecule-1 (ICAM-1) receptor (ID50: CD4+ T cells, 1.9 microM; CD8+ T cells, 1.5 microM) by mibefradil seems to be responsible for the decreased adhesion and penetration rates. Reduction of intracellular F-actin in T lymphocytes could diminish cell locomotion. In conclusion, the potent suppressive properties of mibefradil support its use as a co-medication in cyclosporin A-based immunosuppressive therapy.
Blaheta
R A
RA
Department of General Surgery, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Hailer
N P
NP
Brude
N
N
Wittig
B
B
Oppermann
E
E
Leckel
K
K
Harder
S
S
Scholz
M
M
Weber
S
S
Encke
A
A
Markus
B H
BH
D000199:Actins / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000633:toxicity; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000187:drug effects; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D020748:Mibefradil; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000633:toxicity
D000199:Actins; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D015815:Cell Adhesion Molecules; D007166:Immunosuppressive Agents; D013764:Tetrahydronaphthalenes; D020748:Mibefradil