Immunosuppressive effects of vermiculine in vitro and in allotransplantation system in vivo.
Vermiculine, a macrocyclic aglycosidic dilactone isolated from Penicillium vermiculatum, has been shown to have immunomodulatory properties. Here, we tested the effects of vermiculine on selected parameters of cell-mediated immunity in vitro and on skin allograft survival in vivo. Vermiculine inhibited in a dose-dependent manner the proliferation of mouse spleen cells stimulated with Concanavalin A ((Con A), i.e. T-cell mitogen), bacterial lipopolysaccharide ((LPS), B-cell mitogen) or with irradiated allogeneic cells. In addition, vermiculine dose-dependently inhibited the production of Thl (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokines and suppressed the production of nitric oxide (NO) by activated macrophages. When compared with cyclosporine (CsA), vermiculine was less inhibitory for IL-2 gene expression and IL-2 synthesis, comparably suppressive on IL-10 production and even more inhibitory for NO synthesis. These observations suggest that vermiculine and CsA inhibit immune reactions by different mechanisms. Treatment of graft recipients with vermiculine or CsA prolonged survival of skin allografts in a mouse model. The combination of both drugs enhanced the survival of allografts significantly more than either drug alone. The results thus suggest that vermiculine is a potential immunosuppressive drug acting by a mechanism distinct from that of CsA, and thus it may be used alone or in combination with other drugs for immunoregulatory purposes.
Zajícová
A
A
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague.
Múcková
M
M
Krulová
M
M
Rychnavská
Z
Z
Holán
V
V
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007783:Lactones / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014181:Transplantation Immunology / Q000187:drug effects*; D014184:Transplantation, Homologous / Q000276:immunology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007783:Lactones; D008934:Mitogens; D009569:Nitric Oxide; C009650:vermiculine