New Immunosuppressive Drugs and Their Role in the Prevention of Islet Xenograft Rejection

Abstract

Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune beta cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.

Effect of various immunosuppressive monotherapies on survival and histopathology of monkey islet xenografts in rats

“…The efficacy of various immunosuppressive drugs in the prevention of islet xenograft rejection (from pig-to-rat) was evaluated by a Swedish group [39]. Prednisolone 20 mg/kg/day was used in combination with CsA and cyclophosphamide.…”