OBJECTIVEWe investigated whether changes in islet autoantibody profile and presence of HLA risk markers, reported to predict rapid b-cell loss in pre-type 1 diabetes, associate with poor functional outcome in islet allograft recipients. RESEARCH DESIGN AND METHODSForty-one patients received ‡2.3 million b-cells/kg body wt in one to two intraportal implantations. Outcome after 6-18 months was assessed by C-peptide (random and stimulated), insulin dose, and HbA 1c . RESULTSPatients carrying HLA-A*24-positive or experiencing a significant autoantibody surge within 6 months after the first transplantation (n 5 19) had lower C-peptide levels (P £ 0.003) and higher insulin needs (P < 0.001) despite higher HbA 1c levels (P £ 0.018). They became less often insulin independent (16% vs. 68%, P 5 0.002) and remained less often C-peptide positive (47% vs. 100%, P < 0.001) than recipients lacking both risk factors. HLA-A*24 positivity or an autoantibody surge predicted insulin dependence (P 5 0.007). CONCLUSIONSHLA-A*24 and early autoantibody surge after islet implantation associate with poor functional graft outcome.The success rate of an intraportal islet graft for achieving insulin independence critically hinges on the amount of donor tissue implanted (1). However, a positive outcome can be counteracted by other factors, including preexisting autoreactive T cells, HLA alloantibodies, or high lymphocyte counts (2-4). In recipients of a sufficiently large intraportal islet allograft (5,6), we investigated whether the presence of HLA-A*24, HLA-DQ2/DQ8, or rising islet autoantibody levels, previously shown to independently predict rapid b-cell loss in prediabetes (7,8), associates with poor functional graft outcome. RESEARCH DESIGN AND METHODS Transplant ProtocolForty-one patients with C-peptide-negative type 1 diabetes (median age 45 years) with a history of recurrent hypoglycemia and negative for preexisting HLA class I and class II antibodies (4) received $2.3 million b-cells (;4,600 islet equivalents)/kg

BackgroundIslet cell transplantation holds a potential cure for type 1 diabetes, but many islet recipients do not reach long-lasting insulin independence. In this exploratory study, we investigated whether serum cytokines, chemokines and adipokines are associated with the clinical outcome of islet transplantation.MethodsThirteen islet transplant patients were selected on basis of good graft function (reaching insulin independence) or insufficient engraftment (insulin requiring) from our cohort receiving standardized grafts and immune suppressive therapy. Patients reaching insulin independence were divided in those with continued (>12 months) versus transient (<6 months) insulin independence. A panel of 94 proteins including cytokines and adipokines was measured in sera taken before and at one year after transplantation using a validated multiplex immunoassay platform.ResultsNinety serum proteins were detectable in concentrations varying markedly among patients at either time point. Thirteen markers changed after transplantation, while another seven markers changed in a clinical subpopulation. All other markers remained unaffected after transplantation under generalized immunosuppression. Patterns of cytokines could distinguish good graft function from insufficient function including IFN-α, LIF, SCF and IL-1RII before and after transplantation, by IL-16, CCL3, BDNF and M-CSF only before and by IL-22, IL-33, KIM-1, S100A12 and sCD14 after transplantation. Three other proteins (Leptin, Cathepsin L and S100A12) associated with loss of temporary graft function before or after transplantation.ConclusionsDistinct cytokine signatures could be identified in serum that predict or associate with clinical outcome. These serum markers may help guiding patient selection and choice of immunotherapy, or act as novel drug targets in islet transplantation.

Background. Clinical islet transplantation is generally conducted within 72 hours after isolating sufficient beta-cell mass. A preparation that does not meet the sufficient dose can be cultured until this is reached after combination with subsequent ones. This retrospective study examines whether metabolic outcome is influenced by culture duration. Methods. Forty type 1 diabetes recipients of intraportal islet cell grafts under antithymocyte globulin induction and mycophenolate mofetil-tacrolimus maintenance immunosuppression were analyzed. One subgroup (n = 10) was transplanted with preparations cultured for ≥96 hours; in the other subgroup (n = 30) grafts contained similar beta-cell numbers but included isolates that were cultured for a shorter duration. Both subgroups were compared by numbers with plasma C-peptide ≥0.5 ng/mL, low glycemic variability associated with C-peptide ≥1.0 ng/mL, and with insulin independence. Results. The subgroup with all cells cultured ≥96 hours exhibited longer C-peptide ≥0.5 ng/mL (103 versus 48 mo; P = 0.006), and more patients with low glycemic variability and C-peptide ≥1.0 ng/mL, at month 12 (9/10 versus 12/30; P = 0.005) and 24 (7/10 versus 6/30; P = 0.007). In addition, 9/10 became insulin-independent versus 15/30 (P = 0.03). Grafts with all cells cultured ≥96 hours did not contain more beta cells but a higher endocrine purity (49% versus 36%; P = 0.03). In multivariate analysis, longer culture duration and older recipient age were independently associated with longer graft function. Conclusions. Human islet isolates with insufficient beta-cell mass for implantation within 72 hours can be cultured for 96 hours and longer to combine multiple preparations in order to reach the desired beta-cell dose and therefore result in a better metabolic benefit.