Biomarkers to predict functional outcome of beta cell therapy trials in type 1 diabetes

Type 1 diabetes is a chronic T-cell-mediated autoimmune disease leading to a major loss of insulin-secreting beta cells, hyperglycemia and – if not well controlled – life threatening complications. Prevention strategies, aiming to arrest or slow the destruction of the beta cells (before or after clinical onset) or to restore a sufficient functional beta cell mass, have shown promising results, but overall benefits were transient and limited to subgroups. This indicates the need for precision medicine and the identification of biomarkers to discriminate responders from non-responders to a given therapy. In this respect, factors associated with rapid beta cell loss in the presymptomatic or peri-onset period of type 1 diabetes, such as antibodies against prominent islet antigens (insulin, GAD, IA-2, zinc transporter 8) and genetic susceptibility markers of type 1 diabetes (HLA-DQ2/DQ8, - A*24, -B*18 and -B*39), are obvious candidates. We took advantage of the data and sample base from the previously reported first randomized placebo-controlled anti-CD3 study and from the islet cell transplantation program of the Center for Beta Cell Therapy in Diabetes. Our data suggest that the presence of insulin autoantibodies shortly after diagnosis, in addition to C-peptide release at study entry, predicts good responsiveness to anti-CD3 treatment. In long-standing patients receiving an intraportal islet allograft, presence of HLA-A*24 and surges in autoantibody levels – most frequently GAD autoantibodies – shortly after implantation associate with poor functional outcome. These results illustrate that immunogenetic biomarkers are capable to identify good responders in beta cell therapy trials, but their nature and meaning may depend on the disease stage and the type of intervention.