Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice

OBJECTIVE—Non–Fc-binding anti-CD3–specific antibodies
represent a promising therapy for preserving C-peptide production
in subjects with recent-onset type 1 diabetes. However, the
mechanisms by which anti-CD3 exerts its beneficial effect are
still poorly understood, and it is questionable whether this
therapeutic approach will prove durable with regard to its ability
to impart metabolic preservation without additional actions
designed to maintain immunological tolerance. We used the NOD
mouse model to test whether rapamycin, a compound wellknown
for its immunomodulatory activity in mice and humans,
could increase the therapeutic effectiveness of anti-CD3 treatment
in type 1 diabetes.
RESEARCH DESIGN AND METHODS—Rapamycin was administered
to diabetic NOD mice simultaneously with anti-CD3
or to NOD mice cured by anti-CD3 therapy. The ability of this
combined therapy to revert type 1 diabetes and maintain a state
of long-term tolerance was monitored and compared with that of
anti-CD3 therapy alone.
RESULTS—Rapamycin inhibited the ability of anti-CD3 to revert
disease without affecting the frequency/phenotype of T-cells.
Rapamycin also reinstated diabetes in mice whose disease was
previously reversed by anti-CD3. Withdrawal of rapamycin in
these latter animals promptly restored a normoglycemic state.
CONCLUSIONS—Our findings indicate that, when combined
with anti-CD3, rapamycin exerts a detrimental effect on the
disease outcome in NOD mice for as long as it is administered.
These results suggest strong caution with regard to combining
these treatments in type 1 diabetic patients