Since type 1 diabetes results from a T-cell mediated beta-cell
destruction, it is conceivable that monitoring islet autoreactive T-cells
offers opportunities to trail pathogenic processes. Indeed, circulating islet
autoreactive T-cells can be measured
reproducibly. These T-cells can be isolated from diabetic pancreata,
their specificities are matched with those detected in human insulitic lesions
in situ and cultured clones isolated from type 1 diabetic patients can
recapitulate insulitis in humanized mouse models, supporting their potential
diabetogenicity. Perhaps more importantly, their frequencies in blood predict
clinical outcome of stem cell therapy and islet transplantation and changes in
their frequencies associate with relapsing disease, while the autoimmune
signature distinguishes different immunotherapeutic strategies, pointing to the
possibility that monitoring these T-cells may stage patients for customized
therapy (personalized medicine) and guide and optimize immunotherapy. Yet, the
difficulty to identify and monitor tissue specific regulatory Tcells (aTregs)
poses a critical gap, while I contend that the range of islet epitopes
currently tested as candidate biomarkers in type 1 diabetes need not be the
most rewarding and relevant spectrum to use as immune correlates of disease
progression, remission and therapeutic intercention. For instance, many
candidate epitopes have been selected on basis of xenogeneic models and high
binding HLA affinity whereas auto-epitopes often possess low binding
affinities, the islet peptide repertoires of the most strongly disease
predisposing HLA-DQcis and -trans molecules have not yet been defined in great
detail and it is conceivable that posttranslationally modified autoantigens,
rather than their native counterpart, prove to be most relevant to disease. The
current knowledge and challenges to discover, validate and apply immune
correlates of disease progression, immune regulation and therapeutic
intervention will be discussed.