Prevention of islet graft destruction in diabetic mice and rats by temporary anti-IL-2 receptor therapy: comparison of different strategies.

THE ABROGATION of IL-2 secretion and/or prevention of IL-2 action (eg, by preventing the binding of IL-2 to its receptor [IL-2R]), have been successfully used to intervene cell-mediated immune reactions as autoimmune or allograft reactions. This concept is based on the inhibition or elimination of specific antigen-activated lymphocytes without induction of changes in the pool of resting lymphocytes. Selective prevention of IL-2/IL-2R interaction can be achieved by different IL-2R binding agents, such as monoclonal antibodies (MABs) directed to the IL-2 receptor, IL-2 toxins, or chimeric proteins consisting of IL-2 fused to immunoglobulins. It is assumed that IL-2 toxins and depleting MABs cause selective elimination of IL-2 receptor bearing (IL-2R) cells. Depleting MABs may eliminate target cells either by antibody-dependent cellular cytotoxicity or by complement-dependent killing. In contrast, the IL-2 toxins enter the cytosol of target cells and inhibit protein synthesis by inactivation of elongation factor-2, which results in cell death. One possible mechanism of action, of nondepleting MABs and IL-2 fusion proteins, could be a direct blocking of IL-2 binding and IL-2 dependent proliferation. However, the concentration necessary for inhibition of IL-2 dependent proliferation has to be very high, which is difficult to reach in vivo. The most likely immunosuppressive mechanism of nondepleting antibodies and potentially also fusion proteins, seems to depend on opsonization of target cells. Coated cells are retained and possibly removed by the reticuloendothelial system. The aim of the present study was to compare the efficacy of IL-2R targeting by using either anti-IL-2R MABs, IL-2 toxins, or an IL-2-immunoglobulin fusion protein to prevent islet autoimmune and/or allogeneic destruction in diabetic rats and mice.