ANALYSIS OF PRIMATE RENAL-ALLOGRAFTS AFTER T-CELL DEPLETION WITH ANTI-CD3-CRM9

Background. FN18-CRM9 is a CD3-specific immunotoxin that is capable of depleting CD3(+) T cells. Pretreatment of rhesus monkeys with this ag ent before transplantation can induce donor-specific tolerance and ''s plit tolerance'' to renal allografts. Methods. Heterotopic renal trans plants were performed on monkeys that received posttransplant FN18-CRM 9. Histological and immunohistological staining, as well as analysis o f the intragraft cytokine profile by reverse transcriptase polymerase chain reaction, was performed on percutaneous allograft biopsies. Resu lts. Experimental monkeys had significant prolongation of allograft su rvival. Although an interstitial, mononuclear cell infiltrate was seen in all of the renal transplants, there was minimal evidence of acute cellular rejection. Histological evidence of alloantibody-mediated dam age was detected 3 to 5 months after transplantation in the monkeys tr eated with FN18-CRM9. Immunohistology demonstrated the reappearance of CD3(+) and CD4(+) T cells, as well as CD20(+) B cells, in the grafts. Cytokine analysis demonstrated expression of interferon-gamma. An int act anti-donor IgG response was seen. Conclusion. Treatment of monkeys with FN18-CRM9 immediately after transplantation significantly prolon gs renal allograft survival. Allograft biopsies demonstrate a lack of acute cellular rejection; however, alloantibody-mediated graft damage and rejection occur, with an intact anti donor IgG response, The intra graft expression of the interferon-gamma may reflect this ongoing hum oral rejection. These data suggest that even a brief period of T-cell allosensitization may lead to humorally mediated allograft damage. Eff orts to achieve tolerance with posttransplant FN18-CRM9 will require m odification of the protocol to deplete T cells before allosensitizatio n exposure or to supplement the posttransplant immunomodification stra tegy.