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in Pancreatic Islets in the Nonobese Diabetic Mouse
Pharmacia & Upjohn, Lund Research Center, Lund, Sweden
The nonobese diabetic (NOD) mouse spontaneously develops autoimmune
insulin-dependent diabetes mellitus (IDDM) and serves as an animal
model for human type I diabetes. TNF-
is known to be produced by
islet-infiltrating mononuclear cells during insulitis and subsequent
ß cell destruction and has been implicated in the pathogenesis of
IDDM. Previously, T cells have been suggested as the main source of
TNF- in the islet infiltrate. However, on immunohistochemical
analysis of TNF- expression in islets, we are able to show that the
staining pattern of TNF- resembles that of dendritic cells (DC) and
macrophages (M
) rather than T cells and that TNF- is expressed in
islets at the very early stages of insulitis when no T cells are
detected. On double staining for TNF- and cell surface markers, we
can demonstrate that TNF- staining clearly correlates with DC and
M, whereas there is a poor correlation with T cells. This feature
was observed at both early and late stages of insulitis. TNF-
expression was also seen in NOD-SCID islets, in addition to a
peri-islet infiltration consisting of DC and M, indicating that T
cells are not required for the early DC and M infiltration and
TNF- expression in islets. In conclusion, our results show that DC
and M are the major, early source of TNF- in the NOD islet
infiltrate and that TNF- can be expressed independently of T cells,
indicating that the early DC and M infiltration and expression of
TNF- are crucial in initiation of diabetes.
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