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Abstract
BackgroundIslet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin–independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal FindingsTwenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters - including time until insulin independence, insulin independence at one year, and C-peptide levels over one year- remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/SignificanceIn this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial RegistrationClinicaltrials.gov NCT00623610
Highlights
Islet cell transplantation has considerable potential as a cure for type 1 diabetes (T1D) [1]
Despite the limited number of patients studied that can be studied in clinical islet transplant trials, significant associations of clinical outcome with immunological parameters were derived from blind analysis of data in a group of 21 islet cell recipients
A structured approach validating our techniques has been implemented by the T Cell Workshop of the Immunology of Diabetes Society founded and directed by our institute, that provided considerable experience and reproducibility [28,29,30,37,38]
Summary
Islet cell transplantation has considerable potential as a cure for type 1 diabetes (T1D) [1]. Other factors are expected to influence shortand long-term function of islet grafts, but their identification is difficult in view of the variability in donor and recipient characteristics in islet transplant protocols. The methods used in our clinical study [3,13] allow to standardize donor tissue for cellular composition and beta cell mass [3] and facilitate further analysis of immune factors. They should help examine whether signs of islet cell auto- and alloreactivity in recipients affect successful clinical outcome independently of graft related variables. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function
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