Assessment of plasma microvesicles to monitor pancreatic islet graft dysfunction: Beta cell- and leukocyte-derived microvesicles as specific features in a pilot longitudinal study

Markers of early pancreatic islet graft dysfunction and its causes are lacking. We monitored 19 type 1 diabetes islet-transplanted patients for up to 36 months following last islet injection. Patients were categorized as Partial (PS) or complete (S) Success, or Graft Failure (F), using the beta-score as an indicator of graft function. F was the subset reference of maximum worsened graft outcome. To identify the immune, pancreatic, and liver contribution to the graft dysfunction, the cell origin and concentration of circulating microvesicles (MVs) were assessed, including MVs from insulin-secreting beta-cells typified by polysialic acid of neural cell adhesion molecule (PSA-NCAM), and data were compared with values of the beta-score. Similar ranges of PSA-NCAM(+)-MVs were found in healthy volunteers and S patients, indicating minimal cell damage. In PS, a 2-fold elevation in PSA-NCAM(+)-MVs preceded each beta-score drop along with a concomitant rise in insulin needs, suggesting beta-cell damage or altered function. Significant elevation of liver asialoglycoprotein receptor (ASGPR)(+)-MVs, endothelial CD105(+)-MVs, neutrophil CD66b(+)-MVs, monocyte CD 14(+)-MVs, and T4 lymphocyte CD4(+)-MVs occurred before each beta-score drop, CD8(+)-MVs increased only in F, and B lymphocyte CD19(+)-MVs remained undetectable. In conclusion, PSA-NCAM(+)-MVs are noninvasive early markers of transplant dysfunction, while ASGPR(+)-MVs signal host tissue remodeling. Leukocyte MVs could identify the cause of graft dysfunction.