For patients with type I diabetes
mellitus (T1DM) who want to control their blood sugar
without the daily insulin injections, constant blood glucose
monitoring or inconvenient dietary restrictions, pancreatic
islet cell transplantation is currently the only way to
go. The minimally invasive procedure promises to be the
next best thing to a cure for diabetes, but for years
scientists have tried in vain to design a transplant technique
that works. Enter the Edmonton Protocol, developed by
Dr James Shapiro, Director of the Clinical Islet Transplant
Program, and his research team at the University of Alberta.
The Edmonton Protocol created quite
a buzz when the team first reported their successful
transplantation in seven patients in the June 2000 issue
of the New England Journal of Medicine. "Islet
transplantation is an exciting new therapy for highly
selected patients with unstable and labile forms of
T1DM — which represents about 7% of the T1DM population,"
says Dr Shapiro. In this year's May 27 issue of Transplantation,
the team presents the longterm evidence for islet transplantation
in a review of its progress over the last decade, which
has now been performed in 471 type I diabetic patients
at 43 institutions worldwide.
FLEETING
INDEPENDENCE
Ten years ago, the first islet cell transplant recipient
remained insulin-independent for only 22 days, and most
who subsequently received islets from a single donor
faced similarly disappointing results. Transplanting
islets obtained from more than one donor might better
the chances of success but the induction of immunosuppressive
treatment with high-dose corticosteroids or anti-T lymphocyte
globulin needed to perform this two-donor transplant
could only be maintained for short periods. It was highly
unlikely that a second donor would become available
within this small window of opportunity. Dr Shapiro
and his colleagues circumvented this problem by freezing
donor islets until needed. However, even with many donors,
the quantity and quality of the donor cells were often
problematic.
Eventually, by adopting glucocorticoid-free
immunosuppressive protocols, the team was able to repeat
transplantation with freshly isolated islets from two
to four donors as needed until the patient achieved
normoglycemia. In doing so, the researchers determined
an appropriate 'islet dose' for successful transplantation:
12,000 islet equivalents (IEQs) standardized per kilogram
body weight. This meant at least 850,000 IEQs would
be needed for a 70kg recipient.
An Edmonton Protocol transplant
is typically performed using a local anesthetic and
takes less than an hour. "Cells are prepared in the
lab and infused into the portal vein in the liver,"
explains Dr Shapiro. "The cells function immediately
and are very effective in rapidly stabilizing glycemic
control."
ISLETS
UNDER ATTACK
But there simply aren't enough islets in one pancreas
to allow a patient to become insulin independent —
current islet isolation techniques are approaching the
theoretical maximum yield of 500,000 IEQs/70g pancreas.
Large numbers of islets are needed, in part, because
50-70% may be lost to a form of host-graft interaction,
termed the instant blood mediated inflammatory reaction
(IBMIR). Islet processing may also induce expression
of inflammatory mediators in the islets, which could
elicit a 'danger signal' recognized by the recipient's
immune system. Over the next 15-60 minutes, the islets
are infiltrated by leukocytes and destroyed.
Of the patients treated using the
Edmonton Protocol, "about 80% can achieve insulin independence
at one year, but this falls to about 50% at three years
and to 15% at five years. But over 80% of grafts continue
to function partially — sufficient to maintain
excellent glycemic control and avoidance of [hypoglycemic
reactions]," explains Dr Shapiro. Unfortunately, partial
islet function creates a new dilemma: should supplemental
insulin be given while continuing immunosuppressive
therapy to support the remaining insulin secretory capacity,
or should immunosuppressive drugs be withdrawn as partial
failure becomes evident?
Before islet transplantation becomes
a more attractive treatment option for diabetic patients,
the 1:1 donor to recipient conundrum needs to be resolved
and effective measures to reduce the number of donors
required, graft rejection and the IBMIR must be developed.
For his part, Dr Shapiro is confident these obstacles
will be overcome, "Living donor islet transplants, antirejection
therapies with minimal side effects and low risk, and
islet growth factors all look promising on the horizon."
Transplantation May 27, 2005;79(10):1304-7
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