Patrick S is a history major whose joy in life is to play
left defenceman on his varsity hockey team. While many
of his teammates in their late 20s mostly worry about
losing their hair — and maybe the playoffs —
27-year-old Patrick would rather not lose the few functional
insulin-producing pancreatic beta cells he has left. You
see Patrick has type I diabetes and his body's immune
system is killing the beta cells, minimizing his ability
to produce insulin.
However, "most endocrinologists
would agree that substituting chronic immune suppression
even for insulin treatment of type I diabetes is not
a safe trade-off," asserts Dr Kevan Herold, an endocrinologist
from Columbia University. This means that, like all
type I diabetics, Pat will have to depend on insulin
injections for the rest of his life. But what if there
was a safer way to rein in the rogue immune response
and prevent further decline in beta-cell function?
IT
LASTS AND LASTS
A short course of anti-CD3 antibody may be just the
ticket, according to the results of a trial investigating
the efficacy and safety of the novel immunomodulatory
therapy. The study was published by Dr Herold's team
in the June issue of Diabetes. "The results show
that there is significant improvement in the C-peptide
response to a mixed meal for at least two years after
the single course of [anti-CD3] treatment," says Dr
Herold, emphasizing that "the effects are in the absence
of continuous immune suppression." C-peptide is used
as a marker of beta-cell function and insulin production.
Type I diabetes is thought to be
a result of the body losing control of its immune system,
with T-cells attacking and destroying the pancreatic
beta cells. CD3 is found on the surface of some T-cells,
and has been an attractive target for researchers looking
to extend the insulin- producing life of beta cells.
Traditional antibodies against
CD3 have the disadvantage of activating the immune system
and causing unwanted side effects. Dr Herold's team
avoided this potential problem by using a mouse anti-CD3
antibody, which they "humanized" by changing a few key
amino acids in its sequence. The resulting antibody
didn't spark the unwanted immune response.
To test the antibody's efficacy,
the researchers recruited 42 patients aged eight to
30 within six weeks of diagnosis for type I diabetes.
The patients received a 10-day course of 'full dose'
antibody. At 3-6 month intervals afterwards, C-peptide
levels were measured as a marker of insulin secretion
as was glycosylated hemoglobin (HbA1C), a marker for
longterm glycemic control.
STILL
GOING STRONG
The diabetic patients still required insulin, but the
researchers found, "after two years, a greater proportion
of the drug-treated patients retained clinically important
insulin production compared with the untreated control
subjects ... After one year, the average C-peptide response
was 97% of the response at study entry in the drug-treated
group, whereas it was 53% of the response at entry in
the control subjects." One-third of the treated patients
actually increased their C-peptides, as compared to
5% of controls. More importantly, stabilizing C-peptide
levels improved longterm glycemic control — average
HbA1C levels remained under 7% for 18 months following
antibody administration.
The benefits of the humanized antibody
came with few side effects, but there's a catch. "After
time there is some loss of the response — maintaining
and improving the response is our next goal," explains
Dr Herold.
Diabetes Jun 2005;54(6):1763-9
For more on diabetes see "Edmonton
Protocol promotes successful islet transplants".
|
