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Alexion Pharmaceuticals, New Haven, CT 06511
Programmed cell death represents an important pathogenic mechanism
in various autoimmune diseases. Type I diabetes mellitus (IDDM) is a T
cell-dependent autoimmune disease resulting in selective destruction of
the ß cells of the islets of Langerhans. ß cell apoptosis has been
associated with IDDM onset in both animal models and newly diagnosed
diabetic patients. Several apoptotic pathways have been implicated in
ß cell destruction, including Fas, perforin, and TNF-
. Evidence
for Fas-mediated lysis of ß cells in the pathogenesis of IDDM in
nonobese diabetic (NOD) mice includes: 1) Fas-deficient NOD mice
bearing the lpr mutation (NOD-lpr/lpr)
fail to develop IDDM; 2) transgenic expression of Fas ligand (FasL) on
ß cells in NOD mice may result in accelerated IDDM; and 3) irradiated
NOD-lpr/lpr mice are resistant to adoptive transfer of
diabetes by cells from NOD mice. However, the interpretation of these
results is complicated by the abnormal immune phenotype of
NOD-lpr/lpr mice. Here we present novel evidence for the
role of Fas/FasL interactions in the progression of NOD diabetes using
two newly derived mouse strains. We show that NOD mice heterozygous for
the FasL mutation gld, which have reduced functional
FasL expression on T cells but no lymphadenopathy, fail to develop
IDDM. Further, we show that NOD-lpr/lpr mice bearing the
scid mutation (NOD-lpr/lpr-scid/scid),
which eliminates the enhanced FasL-mediated lytic activity induced by
Fas deficiency, still have delayed onset and reduced incidence of IDDM
after adoptive transfer of diabetogenic NOD spleen cells. These results
provide evidence that Fas/FasL-mediated programmed cell death plays a
significant role in the pathogenesis of autoimmune
diabetes.
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