Partial inhibition of allograft arteriosclerosis (chronic rejection) by 15-deoxyspergualin.
15-deoxyspergualin (DSG) is an immunosuppressive drug that suppresses monocyte/macrophage function and/or T cell induction and early differentiation of B lymphocytes. It is as effective as cyclosporine in the prevention of acute rejection. We have investigated the effects of DSG on rat aortic allograft arteriosclerosis (chronic rejection). DSG was administered to the recipient rat at a dose of 0.3-10 mg/kg/day i.p. for 1-3 months, after which recipients were sacrificed. Histological changes were quantitated from paraffin sections. DSG is effective in chronic rejection in rat aortic allografts and reduces all three manifestations in the vascular wall--adventitial inflammation, media necrosis, and intimal thickening. At the dose of 1.0 mg/kg/day we demonstrated significant inhibition of adventitial inflammation from 10.6 point score units (psu) to 4.7 psu (P < 0.05), of media necrosis (P = 0.004) and of intimal thickening from 2.9 psu to 0.8 psu (P = 0.008). The therapeutic window was small in the long-term experiment. Doses of 3-10 mg/kg/day were toxic and 0.3 mg/kg/day was ineffective. In vitro smooth muscle cell proliferation was not inhibited by DSG and in the in vivo carotic denudation model DSG had no inhibitory effects either. These results suggest that DSG works via suppression of the immune/inflammatory response rather than via a direct antiproliferative effect on smooth muscle cells.
Transplantation Laboratory, University of Helsinki, Finland.
A
A
Räisänen-Sokolowski
S
S
Yilmaz
G
G
Tufveson
P
P
Häyry
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection / Q000517:prevention & control*; D006146:Guanidines / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous / Q000473:pathology
D006146:Guanidines; D006454:Hemoglobins; D007166:Immunosuppressive Agents; C037258:gusperimus