TNF-alpha blockade during islet transplantation in immunosuppressed recipients: a study on in vitro, clinical, and CITR registry-derived data

Introduction: Allogeneic islet transplantation is performed in patients with complicated diabetes mellitus. Despite its promising results, a major problem that remains is early islet graft loss. This is mostly due to the immediate blood-mediated immune response (IBMIR), which leads to significant islet loss shortly after infusion. Etanercept is currently used to mitigate IBMIR by blocking TNF-α and is widely used in peri-transplantation strategies. Most data showing improved graft outcome after TNF-α blockade are from islet transplantation alone patients, who do not use immunosuppression (IS) at the time of islet transplantation (ITx). We hypothesized that ITx recipients that already use IS, e.g. islet-after-kidney recipients, benefit less from TNF-α blockade. Methods: Using a pre-post implantation strategy, clinical graft outcome was compared between ITx recipients with IS that had received etanercept during ITx and a control group that had not received etanercept between 2008 - 2017 at the Leiden University Medical Center. Beta score as a measure of graft function was assessed before and 3 months after ITx. In addition, we extracted 2.5 month clinical outcome data from the Collaborative Islet Transplant Registry (CITR) on ITx recipients with IS. During in vitro experiments, the TNF-α response of circulating mononuclear cells was measured after addition of allogeneic islets to whole blood from patients with IS and from healthy controls during 360 minutes. Culture medium without islets was used as control. Results: TNF-α response significantly increased when blood from controls (n=9) was exposed to islets (AUCTNF-α 9057±3202 pg/360 min [islets] vs 5992±2118 pg/360 min [control medium]; p=0.010). This response to both islets and control medium was significantly higher (p=0.012 and p=0.020, resp.) compared to that in patients with IS (n=8), where TNF-α was lower and did not increase significantly (AUCTNF-α 5470±2446 pg/360 [islets] vs 2131±953 pg/360 min [control medium]; p=0.27). Beta score increased from 3.1±1.7 to 4.3±2.7 (p=0.23) in the etanercept group and from 3.6±2.1 to 6.3±1.9 (p=0.052) in controls, with no significant difference in beta score three months after ITx (p=0.18). In 265 ITx recipients (169 with, 96 without etanercept) from the CITR database, preliminary analyses on graft functional outcomes did not show a significant difference in AUC C-peptide during MMTT (72.0 (0.65 – 201.67) vs 43.5 (0.83 – 239.6), p=0.689) and insulin independence (44.4% vs 47.1%, p=0.695) between the two groups. Conclusions: Peri-transplant etanercept treatment is not associated with better islet graft outcome in previously immunosuppressed patients, which may be due to a mitigated TNF-α response.