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

Scriptie/masterproef: Doctoral Thesis


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.
Datum Prijs21 jun 2016
Toekennende instantie
  • Vrije Universiteit Brussel
BegeleiderFrans Gorus (Promotor), Bart Keymeulen (Promotor), Pieter In 'T Veld (Jury), Bert Bravenboer (Jury), Ellen Anckaert (Jury), Christian Demanet (Jury), Lorenzo PIEMONTI (Jury), H-J Aanstoot (Jury) & K. Casteels (Jury)

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