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.
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 beta-cells, and a cure for type 1 diabetes would require not only tolerance induction but also recovery of the functional beta-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 beta-cell destruction enables islet regeneration to occur. We find no evidence that such monoclonal antibody therapy results in either regeneration of insulin-secreting beta-cells or of increased proliferation of islet beta-cells.
Phillips
Jenny M
JM
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB21QP, U.K.
O'Reilly
Lorraine
L
Bland
Chris
C
Foulis
Alan K
AK
Cooke
Anne
A
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008875:Middle Aged; D010179:Pancreas / Q000166:cytology / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D007328:Insulin; D005934:Glucagon