Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation

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Abstract

Background: Islet 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 Findings: Twenty-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 1A-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome. Conclusions/Significance: In 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. © 2008 Huurman et al.

Figures

  • Figure 1. CONSORT-style flowchart of 24 consecutive islet cell transplantation recipients.
  • Table 1. Recipient characteristics
  • Figure 2. Kaplan-Meier curves showing cumulative insulin independence after b-cell transplantation, stratified for A) pretransplant cellular autoimmunity and B) pre-transplant presence of autoantibodies. Continuous lines represent patients without reactivity to autoantigens, striped lines patients with reactivity to a single antigen, and dotted lines patients with reactivity to two antigens (or three in the case of autoantibodies). doi:10.1371/journal.pone.0002435.g002
  • Figure 3. A) C-peptide levels stratified for cellular autoimmune status before and after transplantation. Total C-peptide levels over one year for patients that are not autoreactive pre- nor post-transplant (2/2, n = 3) only pre- (+/2, n = 6) or only post-transplant (2/+, n = 5), and both pre- and post transplant (+/+, n = 4). Areas under the curve differ significantly between groups (p = 0.009, one-way ANOVA). Horizontal lines represent average C-peptide level per group. B) average basal C-peptide levels (black lines)6SD (grey areas) over time for the four different groups. Differences between 2/2 and +/+ and between 2/+ and +/+ remain significant after Bonferroni correction. Pre-transplant autoreactivity significantly reduces total Cpeptide production (p = 0.006, unpaired t-test). doi:10.1371/journal.pone.0002435.g003
  • Figure 4. Influence of pre-transplant T cell autoreactivity stratified for total injected b-cell mass. Shown are pre-transplant T cell autoreactivity and achievement of insulin independence for patients receiving more or less than the median total injected b-cell mass (the single patient receiving the median b-cell mass is excluded). Groups are compared by Fischer exact test. doi:10.1371/journal.pone.0002435.g004

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CITATION STYLE

APA

Huurman, V. A. L., Hilbrands, R., Pinkse, G. G. M., Gillard, P., Duinkerken, G., van de Linde, P., … Roep, B. O. (2008). Cellular islet autoimmunity associates with clinical outcome of islet cell transplantation. PLoS ONE, 3(6). https://doi.org/10.1371/journal.pone.0002435

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