EFFECT OF LEFLUNOMIDE AND CYCLOSPORINE ON GRAFT-SURVIVAL AND CHANGES IN LYMPHOCYTE PHENOTYPES IN A RAT-HEART ALLOTRANSPLANTATION MODEL

Cyclosporine-A (CSA) and leflunomide (LF) can delay or prevent organ g raft rejection. We investigated the combination of LF, CSA and splenec tomy on graft survival and changes in lymphocyte phenotypes (LP) in a rat allotransplantation model. In the study 19 Lewis rats were splenec tomized prior to heterotopic heart transplantation. SPRD rats served a s donors. The recipients were divided into three groups: A - five anim als received CSA and LF for two weeks, B - five received intermittent CSA and LF for the whole investigation period and C - nine received no drug therapy. LP was quantified relatively by flow cytometric analysi s. We found that graft survival was longer in group A (median 155 days , range 52-348) and B (341, range 338-342), compared to group C (8, ra nge 7-13). The histological examination, however, revealed signs of re jection in all allografts. In group A all except one animal and in gro up C the morphological changes were characterized by severe acute reje ction. In contrast, one animal in group A and all the animals in group B revealed signs of moderate acute rejection and in most animals sign s of chronic rejection were also found. The reduction of Pan-T and CD4 + cells in group B compared to the control group was associated with n o clinical rejection, while the increase of CD8+ cells in group C and partly in group A (except for animal 3) was associated with clinical r ejection. No difference in LP was detected between groups A and B in t he study period. We concluded that a combination of CSA, LF and splene ctomy was efficient in preventing clinical rejection, however, there w ere signs of rejection morphologically even in animals without clinica l rejection. The changes in LP over time could not predict the clinica l outcome. However, increase in CD8+ cells was highly associated to cl inical rejection among nonimmunosuppresed animals.