EFFECTS OF LEFLUNOMIDE AND DEOXYSPERGUALIN IN THE GUINEA-PIG-]RAT CARDIAC MODEL OF DELAYED XENOGRAFT REJECTION - SUPPRESSION OF B-CELL AND C-C-CHEMOKINE RESPONSES BUT NOT INDUCTION OF MACROPHAGE LECTIN

Background. If complement (C) activation is prevented or the host is C depleted, discordant vascularized xenografts undergo delayed xenograf t rejection (DXR), characterized by graft infiltration by macrophages (MO) and natural killer (NK) cells, endothelial cell activation, and w idespread fibrin deposition. Given a lack of effect of T cell-directed therapies on development of DXR, we evaluated two novel agents, 15-de oxyspergualin (DSG) and leflunomide (LEF), with reported anti-B-cell a nd/or anti-MO actions. Methods. DSG: and LEF were administered to C-de pleted, splenectomized rat recipients of guinea pig cardiac xenografts , and their effects on graft survival and production of anti-guinea pi g antibodies were determined. Serial intragraft events were studied by immunohistology using monoclonal antibodies to rat leukocytes, cytoki nes, and novel proteins, including rat MO lectin, which in other syste ms is important to MO binding, activation, and target cell killing. Re sults. Median graft survival was 62 hr in cobra venom factor (CVF)-tre ated controls versus 108 hr (DSG), 129 hr (LEF), and 120 hr (DSG and L EF; all groups P<0.01 vs. CVF alone). LEF and DSG each decreased (immu noglobulin M [IgM]) or abrogated (IgG) posttransplant production of an ti-guinea pig antibodies, Immunohistologic studies showed that each ag ent also inhibited graft infiltration by Nh and T cells, and expressio n of various cytokines, including the chemokine monocyte chemoattracta nt protein-1 (MCP-1), but did not affect the tempo or extent of MO inf iltration. Consistent with this, the rapid induction of MO lectin post xenografting, and induction of MO lectin by rat MO exposed to guinea p ig cells in vitro, were unaffected by therapy with DSG and/or LEF. Con clusions. LEF or DSG; along with CVF can result in the longest prolong ation of xenograft survival yet reported in this model, in conjunction with a dampening of host mononuclear cell responses, including suppre ssion of B cell activation. However, the persistent influx of MO in th is model, despite lack of C-, Fc receptor-or apparent chemokine-depend ent mechanisms, suggests the presence of additional mechanisms for cel l recruitment and activation. It was of importance that, in this regar d, although MO depletion is technically difficult and can lead to unde sired effects, the demonstration of rapid MO lectin induction postxeno grafting indicates opportunities for blockade of MO recruitment and fu nctions during DXR by use of anti-MO lectin monoclonal antibodies or a dministration of competing sugars.