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Patients With Chronic Pancreatitis Have Islet Progenitor Cells in Their Ducts, but Reversal of Overt Diabetes in NOD Mice by Anti-CD3 Shows No Evidence for Islet Regeneration

¹ Department of Pathology, University of Cambridge, Cambridge, U.K
² The Walter and Elisa Hall Institute of Medical Research, Parkville, Victoria, Australia
³ Department of Pathology, Royal Infirmary, Glasgow, Scotland

Address correspondence and reprint requests to Prof. Anne Cooke, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB21QP, U.K. E-mail: ac{at}mole.bio.cam.ac.uk

Abbreviations: BrdU, bromodeoxyuridine; PDX, pancreatic duodenal homeobox

Monoclonal antibodies to T-cell coreceptors have been shown to tolerise autoreactive T-cells and prevent or even reverse autoimmune pathology. In type 1 diabetes, there is a loss of insulin-secreting ß-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the functional ß-cell mass. Although we have previously shown that diabetic mice have increased numbers of ductal progenitors in the pancreas, there is no evidence of any increase of insulin-secreting cells in the ducts. In contrast, in the adult human pancreas of patients with chronic pancreatitis, we can demonstrate, in the ducts, increased numbers of insulin-containing cells, as well as cells containing other endocrine and exocrine markers. There are also significantly increased numbers of cells expressing the homeodomain protein, pancreatic duodenal homeobox-1. Anti-CD3 has been shown to reverse overt diabetes in NOD mice; thus, we have used this model to ask whether monoclonal antibody–mediated inhibition of ongoing ß-cell destruction enables islet regeneration to occur. We find no evidence that such monoclonal antibody therapy results in either regeneration of insulin-secreting ß-cells or of increased proliferation of islet ß-cells.

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