Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

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

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…We could not identify major effects of maintenance therapy. A small group of patients who did not receive induction therapy experienced higher incidence of T1D recurrence compared to those who had induction; regimens were not compared in a randomized trial and patients were enrolled in different time periods, yet the findings suggest that induction may protect from recurrence, possibly by depleting autoreactive T cells present at transplantation, which could include memory autoreactive T cells that can be reactivated on follow‐up 36, 37. Importantly, most (157/223, 70%) of the patients studied had been treated with our current immunosuppressive protocol 38, 39, 40.T1D recurrence has continued to occur with the current regimen with an overall prevalence of about 4.6% during the 2000–2013 period.…”

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

“…There is cumulative evidence that CD8 + T cells may participate as effectors and as regulators in autoimmune diseases [16,[24][25][26][27][28]. A clear inhibitory interaction between regulatory CD8 + and autoreactive CD4 + T cells was found in experimental autoimmune encephalomyelitis [25,29] and also in human autoimmune diabetes [30][31][32]. In a mouse model of experimental autoimmune encephalomyelitis, CD8 + /CD28 − T cells provided protection by inhibiting upregulation of co-stimulatory molecules on antigenpresenting cells, thereby inhibiting activation and clonal expansion of autoaggressive CD4 + cells [26].…”

“…However, our study indicates that the scenario of autoimmune tolerance is more complex with respect both to the role of defined lymphatic compartments, and to a permissive function of CD8 + T cells for induction of Tregs and an anti-inflammatory cytokine state. Additionally, the balance between autoreactive and protective T cell milieu plays an important role in the recurrent autoimmunity in islet transplantation [32]. With this knowledge, it will be possible to refine immunomodulatory strategies at different stages of autoimmunity and thereby control autoaggressive T cells.…”

Immunogenicity of human embryonic stem cell-derived beta cells

“…Partial early loss of grafts through innate immune reactions may be overcome by transplanting more cells or by choosing an alternative site to the liver. However, both recurrent autoimmunity and alloreactive responses remain a persistent threat to transplanted human-derived beta cells despite immunosuppression [9][10][11]. Additionally, alloreactive responses provoked by a graft can be a risk for future transplantations [12][13][14].…”