Synergistic Effects of Drugs continued...

Possible Dosing Regimens

Grafts survive very effectively on rats with prolonged ATG treatment in three dose regimens in the present study yet Linomide proved to completely nullify the effect of ATG in the lowest dose group. This could be explained by the fact that a low dose of ATG causes an incomplete depletion of T-cells, making it possible for Linomide to stimulate the remaining cells to reject the transplant. In rats receiving 0.1 ml ATG, Linomide was given for 10 days without any effect on the graft survival. One possible explanation for this is that the higher ATG dose results in an insufficient number of immunocompetent cells on which Linomide can exert its effect.

This is supported by the reduced survival rates in the group receiving 0.2 ml ATG and Linomide for 3 weeks after the transplant. The major theoretical advantage of multiple drug therapy is to increase the immunosuppressive effects while reducing side effects. The best way of combining ATG and CyA therefore seems to be an early high dose of ATG, followed by immediate CyA treatment, before immunocompetent cells are allowed to proliferate. This is also how the sequential ATG therapy is used in many treatment centers, although ATG usually is given after instead of before transplantation. Giving ATG for a prolonged period during the sensitive induction period after transplantation could theoretically deplete useful T-cells with suppressor capability, resulting in an abrogated tolerance induction.

In summary, this study shows for the first time a synergistic effect between ATG and CyA in promoting tolerance of transplants. The University of Goteborg researchers found that Linomide effectively prevented tolerance induction and promoted rejection in CyA as well as in ATG treated and transplanted rats.

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