Can the immunosupressive effect of perioperative single high-dose antithymocyte globulin administration in kidney allograft recipients be due to apoptosis of activated lymphocytes?

Abstract

DESPITE that the new, potent immunosuppressive medications (tacrolimus, mycophenolate mofetil, sirolimus) have been widely used, the monoclonal or polyclonal antilymphocytic antibodies are still being used in organ transplant recipients. Antibodies are more often used as induction therapy, particularly in high-risk patient populations. Until recently the induction therapy consisted of the use of antibodies for 7 to 12 days after transplantation and withdrawal of calcineurin inhibitors for the first week. Antithymocyte globulin (ATG) treatment induces a profound depletion of peripheral blood lymphocytes. The precise mechanism of action of ATG remains largely unknown. Various mechanisms have been proposed to explain lymphocyte depletion, including complement-mediated cytolysis or clearance of lymphocytes by opsonization and phagocytosis by macrophages. Apoptosis has also been suggested as a possible mechanism of lymphocyte depletion by ATG. This biologic agent has been the mixture of polyclonal antibodies with various lymphocyte surface antigens. It contain antibodies to CD2 and CD3, which accounts for the mitogenic properties. Published results of in vivo and in vitro tests indicate that the effect of ATG can be due to binding to CD2 , CD3 , CD4 , CD4 /CD28 , CD5 , CD7 , LFA-1 , and ICAM-1 lymphocytes. The rationale for the perioperative use of monoclonal or polyclonal antibodies is based on the fact that sensitization of the recipient’s immune system begins immediately after revascularization of the graft. ATG in that respect seems to have wider specificity than new anti-IL2 receptor antibodies. Kaden et al were the first to propose the perioperative administration of a single, high dose of ATG in patients receiving cadaveric kidney transplantation. Their positive results prompted other investigators to use the same protocol. In these studies the basic immunosuppressive protocol consisted of Neoral (cyclosporine), steroids, and azathioprine. Our preliminary results of a prospective randomized study of in vivo immunosuppressive activity of high, single dose (9 mg/kg) of ATG administered immediately before revascularization to kidney allograft recipients receiving triple-drug immunosupression (Neoral, steroids, mycophenolate mofetil) showed that this protocol is effective and allowed good patient and graft 2-year survival (Table 1). The follow-up ranged from 24 months up to 3 years. There were no side effects or differences in serious adverse events reported during observation period. The incidence of delayed graft function occurred, although not significantly, more often in the control group (16 of 39 vs 20 of 40 patients). There was no difference in 2-year patients and graft survival between groups. Two-year graft survival in ATG-treated patients with and without acute tubular necrosis (ATN) was 80% vs 90%. In the control group, the graft survival in patients with and without ATN was 75% and 95%, respectively. The onset of acute rejection was delayed and the number of rejection episodes were lower in ATG-treated patients. The difference between groups in that respect was statistically significant. A higher number of lost grafts in the control group correlated with delayed graft function.