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.

Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice

“…AAGP-supplemented islets showed significantly reduced expression of IL-1b and IL-6 along with decreased secretion of KC and TNF-a, despite exposure to Tac in culture. These cytokines and chemokines are key participants in the posttransplant inflammatory response and subsequent adaptive immunity activation (42) as well as vital elements in the early clinical posttransplant phase (30). These findings are consistent with previous experiments showing reduced expression of cyclooxygenase-2 expression in HeLa cells exposed to increasing concentrations of IL-1b in the presence of AAGP (17).…”

“…For cytokine and cleaved caspase-3 quantification, the islet grafts were excised from the kidney and bisectioned, with one section flash frozen in liquid nitrogen and stored at 280°C and the other formalin fixed and processed for TUNEL quantification. Tissue samples were subsequently lysed in acid buffer as reported previously (30). Cytokine and cleaved caspase-3 determination was adjusted per gram of tissue.…”

“…Islets were transplanted under the kidney capsule as described previously (29). A minimal islet dose was used to stress the model and maximize covert toxicity (30)(31)(32).…”

Thiobenzothiazole-modified Hydrocortisones Display Anti-inflammatory Activity with Reduced Impact on Islet β-Cell Function

“…For example, anakinra, which interferes with IL-1␤ signaling, and etanercept, which targets the TNF-␣ pathway, have been combined with greater efficacy over either intervention alone in a promising preclinical report (58). New compounds, such as MS4, may thus expand the repertoire of available anti-inflammatory molecules, giving the possibility of additional combinations with even greater efficacy than available currently.…”

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

“…Recent clinical studies in islet transplantation have used etanercept, a soluble receptor antagonist to TNF-α, alone [47] or in combination with anakinra (a soluble receptor antagonist to IL-1β [19]), to improve islet engraftment using marginal mass islet transplants. The improved outcome of clinical transplants with the combined use of etanercept and anakinra were further corroborated in marginal mass human islet transplants in immunodeficient mice [48]. Taken together, these reports emphasise the need to control inflammatory cytokines during the early transplant period to improve islet engraftment.…”