Synergistic effect of anti-T cell receptor monoclonal antibody and 15-deoxyspergualin on cardiac xenograft survival in a mouse-to-rat model

Background. Successful xenograft transplantation faces several obstacles in cluding the presence of xenoantibodies, natural killer cell- and macrophage -mediated rejection, and T lymphocyte activation. Methods. A mouse-to-rat cardiac xenograft model was used to examine the syn ergistic effect of anti-T cell receptor (TCR) monoclonal antibodies (mAb) a nd 15-deoxyspergualin (DSG) on graft survival. Results. Pretransplantation injections (days -5, -3, and -1) of anti-TCR mA b (500 mu g/kg/day) combined with continuous i.p. infusion of DSG (5 mg/kg/ day) from day -7 to 28 significantly prolonged graft survival compared to u ntreated controls (3.3+/-0.5 vs. 44.2+/-5.6 days, P<0.001). Postoperative s plenectomy combined with discontinuation of all other treatment on day 28 e nhanced graft survival in rats treated with anti-TCR mAb and DSG to 71.0+/- 2.5 days. Histological examination of grafts showed characteristic signs of vascular rejection: interstitial edema and hemorrhage, and polymorphonucle ar cell infiltration. Anti-mouse antibody titers in recipients were increas ed upon rejection in each group that received a xenograft. Flow cytometry a nalysis showed a markedly decreased T cell population and a relatively incr eased mature B cell population (IgM(bright)/IgD(dull)) in spleens of rats t reated with anti-TCR mAb and DSG on day 28. Conclusions. The mechanism of prolonged xenograft survival in this model ma y include inhibition of antibody production by arrest of B-cell maturation during development from IgMd(dull)/IgD(bright) mature a cells to antibody p roducing cells, and inhibition of T cell activation. The rejection seen in our model may be caused by xenoreactive antibodies and may be associated wi th T cells, natural killer cells, and macrophages.