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Reversal of established
autoimmune diabetes by
restoration of endogenous beta
cell function.
Immunobiology Laboratory,
Harvard Medical School and
Massachusetts General Hospital,
Charlestown, Massachusetts
02129, USA.
In NOD (nonobese
diabetic) mice, a model of
autoimmune diabetes, various
immunomodulatory interventions
prevent progression to diabetes.
However, after hyperglycemia is
established, such interventions
rarely alter the course of
disease or allow sustained
engraftment of islet
transplants. A proteasome defect
in lymphoid cells of NOD mice
impairs the presentation of self
antigens and increases the
susceptibility of these cells to
TNF-alpha-induced apoptosis.
Here, we examine the hypothesis
that induction of TNF-alpha
expression combined with
reeducation of newly emerging T
cells with self antigens can
interrupt autoimmunity.
Hyperglycemic NOD mice were
treated with CFA to induce TNF-alpha
expression and were exposed to
functional complexes of MHC
class I molecules and antigenic
peptides either by repeated
injection of MHC class I matched
splenocytes or by
transplantation of islets from
nonautoimmune donors.
Hyperglycemia was controlled in
animals injected with
splenocytes by administration of
insulin or, more effectively, by
implantation of encapsulated
islets. These interventions
reversed the established beta
cell-directed autoimmunity and
restored endogenous pancreatic
islet function to such an extent
that normoglycemia was
maintained in up to 75% of
animals after discontinuation of
treatment and removal of islet
transplants. A therapy aimed at
the selective elimination of
autoreactive cells and the
reeducation of T cells, when
combined with control of
glycemia, is thus able to effect
an apparent cure of established
type 1 diabetes in the NOD
mouse.
PMID: 11435458 [PubMed
- indexed for MEDLINE]
