SYNERGISTIC ACTIONS OF THE VITAMIN-D ANALOG MC-1288 AND 15-DEOXYSPERGUALIN IN XENOTRANSPLANTATION

The vitamin D analogue MC 1288 (20-epi-1 alpha,25-dihydroxycholecalcif erol) effectively postpones rejection of cardiac, intestinal, skin, an d aortic allografts. MC 1288 binds to the vitamin D receptor and is th us assumed to exert its immunosuppressive effects via the same mechani sms as 1 alpha,25-dihydroxycholecalciferol, the active form of vitamin D. 1 alpha,25-Dihydroxycholecalciferol has been demonstrated to inhib it the production of various cytokines (interleukin-2, interferon-gamm a, granulocyte macrophage colony-stimulating factor, and interleukin-1 2) and to prevent B lymphocyte secretion of immunoglobulins, In the pr esent study MC 1288 was evaluated for its ability to prevent rejection of mouse-to-rat cardiac xenografts, alone and in combination with 15- deoxyspergualin (DSG). Combined treatment with MC 1288 (given days -1 to 9) and DSG (given day -1 and onward) postponed rejection from day 3 .0 (untreated recipients) until day 19.5, In rats treated with MC 1288 or DSG as monotherapy, rejection occurred after 3.0 and 7.5 days, res pectively. Functioning grafts, obtained on day 9 from recipients treat ed with MC 1288 and DSG in combination, displayed an almost normal mor phology without any obvious deposition of immunoglobulins in the vesse ls of the grafts and with just a few infiltrating cells. Thus, we have demonstrated synergistic actions of MC 1288 and DSG in delaying rejec tion of xenografts. Analysis of cellular infiltration, immunoglobulin deposition and graft survival times in the various treatment groups in dicate a combined inhibitory effect of these two drugs on the level of macrophage effector function, direct or indirect via T lymphocytes, a s well as on antibody production.