Antithymocyte Globulin and Cyclosporin A are Synergistic in an Experimental Transplantation Tolerance Model in the Rat

Abstract

The aim of the present investigation was to study the possible synergistic effect between cyclosporin A (CsA) and antithymocyte globulin (ATG), using the potent immunostimulator, Linomide. DA rats were transplanted with a PVG/c heart to the neck vessels, and the recipients were treated for 10 days with oral CsA (10mg/kg), oral Linomide (160mg/kg) and/or ATG, which was given as a single dose of either 0.02 ml, 0.1 ml or 0.2 ml prior to transplantation. Rats given a combination of ATG and Linomide or CsA and Linomide were used as controls. Synergism between CsA and ATG was tested using the two immunosuppressive drugs given in combination in order to override the challenge of Linomide. CsA or ATG treatment alone resulted in rats with long-term surviving grafts. Addition of Linomide to CsA-treated recipients was followed by early graft rejection. Similarily, Linomide triggered rejection in rats given a low dose of ATG and in recipients given a high dose of ATG if Linomide treatment was prolonged to 21 days. The combination of ATG, CsA and 21 days of Linomide resulted in a significantly prolonged graft survival compared with either ATG + Linomide or CsA + Linomide. These findings demonstrate the synergistic capacity of ATG and CsA in combined immunosuppressive therapy.

Tolerance or Rejection: A Delicate Balance as Judged by Exposure of Heart‐Transplanted Rats to the Immunomodulator Linomide®

“…In one system, namely that of ATG-induced tolerance, the cause of tolerance may well be suppressor cells [40]. However, this tolerance induction is severely hampered by Linomide Ò [11]. It is tempting to interpret our present ®ndings as suggesting that suppression can be stimulated with the immunostimulator Linomide Ò .…”

“…In cardiac transplant models, for instance, exposure to Linomide Ò has been reported to abolish all of the immunosuppressive effect of cyclosporine A (CsA) [4] or of prednisone [5], to reduce the effect of deoxyspergualine in a dose-dependent manner [6] and to eliminate almost all of the effect of tacrolimus [7], mycophenolate mofetil [8] or le¯unomide [9] and its analogues [10]. Polyclonal antibody-mediated immunosuppression with antithymocyte globuline (ATG) is also impaired by Linomide Ò [11], however, the effect of monoclonal anti-CD4 antibody is not [12].…”

Mechanisms and Rescue Strategies of Calcineurin Inhibitor Mediated Tolerance Abrogation Induced by Anti-CD4 mAb Treatment

“…But it has to be pointed out again that in some reports no detrimental effect of an additional CNI treatment could be reported (22,24,48). Also for the induction of microchimerism, the only so far successful approach to achieve tolerance in patients, conflicting data on synergy/compatibility or antagonism of CNIs have been published in experimental models (17,48).…”

“…Effect of concomitant application of CsA on allograft survival has been investigated in tolerance induction protocols based on bone marrow-mediated induction of chimerism (17)(18)(19), costimulatory blockade (16,20,21) but also nondeletional targeting of co-receptors such as CD4 and CD8 (22,23). When reviewing these studies it appears that regardless of the protocol used concomitant CsA treatment acts synergistic or has no effect when the tolerance protocol used on its own does not or to a rather low extent induce permanent acceptance (19,22,24,25). In contrast, when using other tolerance induction protocols with a high percentage of permanent graft acceptances, an additional CsA treatment can but does not always lead to tolerance abrogation (17,20,23,26,27).…”