title: Anakinra potentiates the protective effects of etanercept in transplantation of marginal mass human islets in immunodeficient mice.
abstract: Anti-inflammatory agents are used routinely in clinical islet transplantation in an attempt to promote islet engraftment. Infliximab, and more recently etanercept, is being used to neutralize tumor necrosis factor alpha, but this tenet is based on limited preclinical data. One group has promoted the potential of combined etanercept with an IL-1 receptor antagonist, anakinra in a small clinical study, but without strong preclinical data to justify this approach. We therefore sought to evaluate the impact of combined anakinra and etanercept in a marginal islet mass transplant model using human islets in immunodeficient mice. The combination of anakinra and etanercept led to remarkable improvement in islet engraftment (control 36.4%; anakinra 53.9%; etanercept 45.45%; anakinra and etanercept 87.5% euglycemia, p < 0.05 by log-rank) compared to single-drug treated mice or controls. This translated into enhanced metabolic function (area under curve glucose tolerance), improved graft insulin content and marked reduction in beta-cell specific apoptotis (0.67% anakinra + etanercept vs. 23.5% control, p < 0.001). These results therefore strongly justify the combined short-term use of anakinra and etanercept in human islet transplantation.
authors: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
authors: M
authors: M
authors: McCall
authors: R
authors: R
authors: Pawlick
authors: T
authors: T
authors: Kin
authors: A M J
authors: AM
authors: Shapiro
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D000068800:Etanercept; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D000068800:Etanercept