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[IP] Perspectives on Islet Transplantation

 " Perspectives on Islet Transplantation" from Medscape

   Arun S. Rajan, MD, MBA   Disclosures

   Recent advances in basic and clinical research have led to remarkable
success in human islet transplantation. At the 62nd Scientific Sessions of
the American Diabetes Association, Camillo Ricordi, MD,[1] University of
Miami, Florida, recipient of the 2002 Outstanding Scientific Achievement
Award of the American Diabetes Association, discussed the scientific
progress that
has resulted in improved clinical outcomes in islet transplantation. Dr.
Ricordi's work and the findings of other investigators presented at this
meeting have generated excitement and renewed hope for a cure for type 1

   The Therapeutic Basis for Islet Transplantation

   Although exogenous insulin therapy remains the cornerstone of treatment
for the majority of patients with type 1 diabetes, islet cell replacement
offers the potential for:
        Freedom from multiple insulin injections or insulin pumps, since
islet cells can make their own insulin.
        Better metabolic control through regulated insulin release, since
the islet cells can intrinsically sense and respond to changes in blood
glucose and other physiologic signals.

   Whole pancreas transplantation offers similar advantages, but is a more
complex surgical procedure associated with significant perioperative
morbidity and mortality. By contrast, islet cell transplantation can be
performed as a minimally invasive procedure.

   Improvements in Islet Isolation Procedures

   Islets are scattered throughout the pancreas and comprise less than 1% to
2% of the entire pancreatic mass. The preparation of purified islets for
transplantation previously entailed crude disruption of the pancreas through
mechanical means (tissue macerators) and/or chemical (enzymatic digestion)
means. These processes caused significant islet cell damage, lower yields,
and reduced viability and function of transplanted islets, which may have
contributed to poor clinical outcomes.

   The development of the Ricordi chamber (Figure), an apparatus that
isolates islets from other pancreatic cells, was a major scientific
breakthrough that offered an automated method for islet isolation. Use of
the Ricordi chamber allows recovery of a higher yield of islets from a
single donor pancreas and permits large-scale islet isolation for
transplantation. Briefly, the procedure entails enzymatic digestion of a
pancreas in a mechanically shaken chamber that is perfused with collagenase
solution circulating in a
   closed loop system. The freed islets pass through a layer of mesh and are
further separated and purified by automated centrifugation. Another advance
has been the availability of highly purified enzymes (eg, Liberase) for
pancreatic digestion. These enzymes contain no endotoxin contaminants and
thereby prolong islet graft survival. These improvements have led to higher
islet yields and viability and have enhanced the feasibility of islet
transplantation as a therapeutic option.

   The Edmonton Protocol for Islet Implantation

   Arguably, the most exciting recent breakthrough in islet transplantation
research has been the development of a unique set of strategies for islet
cell replacement.
The Edmonton Protocol (named for  the islet transplantation group at the
University of Alberta, Edmonton, Canada) consists of the following

        Use of the Ricordi automated method to obtain highly purified,
endotoxin-free islets.

        Minimal ischemia time and use of freshly isolated islets.

        Use of a large islet mass (~10,000 islet equivalents/kg), with most
patients receiving at least 2 islet transplants.

        Use of a potent steroid-free immunosuppression protocol consisting
of sirolimus, tacrolimus, and an anti-IL-2 receptor monoclonal antibody
(daclizumab). Tacrolimus and sirolimus act synergistically in vivo and
dramatically reduce acute rejection

   The actual implant is performed through a simple procedure using
percutaneous transhepatic access to deliver the islet cells into a portal
vein via a catheter under angiographic monitoring. Most patients are
discharged within 24 hours of the procedure.

   The cause for excitement in the field has been the remarkable success
rate for clinical outcomes with the Edmonton protocol. Results from the
islet transplant registry for islet transplants over the previous decade
(1990-1999) indicated rather poor outcomes for islet transplant recipients,
with only 8% showing insulin independence beyond 1 year. By contrast, when
first reported in
2000,[2] 7 out of 7 patients (100%) undergoing the Edmonton protocol
remained insulin-independent after a mean follow-up of
approximately 12 months, with an average duration of ~30 days between
transplants (to reach optimal islet mass). No evidence of perturbations due
to hypoglycemia was reported in the transplant recipients.

   Current follow-up data on 19 patients, presented by Edmond A. Ryan, MD,
University of Alberta, Edmonton, Canada, and colleagues[3] continue to show
good outcomes, with a > 80% rate of insulin independence at 1-year follow-up
and a > 60% rate of insulin independence at 2-year follow-up. In an attempt
to reproduce the success of the Edmonton group, parallel clinical trials
have been initiated at 9 islet transplant centers worldwide, under the
auspices of the Immune Tolerance Network.

   Achieving Immune Protection

   A major obstacle to success in islet transplantation is the loss of the
islet graft due to immune responses. However, recent strategies to overcome
this hurdle and enhance tolerance are under clinical investigation and have
shown promising results. These strategies include:

        Prevention of T-cell activation using anti-CD3 monoclonal
        Costimulatory blockade of T-cell activation using anti-CD154
monoclonal antibodies.
        Induction of mixed chimerism using donor-specific bone marrow
infusions. This strategy allows chimeric recipients to accept organs or
cells from the same donor.

   An alternate strategy to immunosuppression and immune tolerance is
immunoisolation. Here the technological goal being pursued is encapsulation
of islets in microcapsules with semipermeable membranes that permit access
to nutrients and oxygen but are impermeable to cells and products of the
immune system. If ongoing animal trials are successful, these approaches may
permit human islet transplantation without immunosuppression.

   Promoting Graft Survival

   In addition to preventing immune destruction of the islet implant, other
strategies are being developed to enhance graft survival.

   One issue relates to the high metabolic demand imposed on the new graft,
which generally is insufficient to replace the intrinsic function of the
normal pancreas containing ~1 million islets. In addition, the
immunosuppressive regimen has a diabetogenic effect,
further increasing the metabolic load on the graft. This issue has been
partially addressed by implanting a larger number of islets and
performing repeated islet transplants in the Edmonton protocol. Strategies
to limit the diabetogenic potential of immunosuppressive drugs are also
being pursued.

   Other approaches include neutralizing the effects of cytokines (eg, tumor
necrosis factor-alpha [TNF-alpha]) using anti-inflammatory compounds (eg,
anti-TNF monoclonal antibody). In animal studies by Zadong Yang, MD,
University of Virginia, Charlottesville, and colleagues,[4] it has been
observed that lisofylline, an anti-inflammatory agent, prevents
autoimmune damage to islets transplanted into nonobese diabetic mice.
Another strategy is to protect islets from apoptosis
(programmed cell death). Annette Plesner, PhD, British Columbia Institute
for Children's and Women's Health, Vancouver, British Columbia, Canada, and
colleagues,[5] conducted in vitro studies of islet cell lines and observed
that beta cells overexpressing XIAP (X-linked inhibitor of apoptosis
protein) are protected from cytokine-regulated cell death. Furthermore,
normal islet cells expressing XIAP that were transplanted into diabetic
recipient mice were resistant to allograft rejection. These studies suggest
that islets engineered with anti-apoptotic genes prior to transplantation
may exhibit greater survival advantage upon engraftment.

   A Note of Caution: Impaired Hypoglycemia Counterregulation in Islet
Transplant Recipients

   In general, clinical outcomes following islet transplantation have been
quite favorable. However, one should be wary of some risks associated with
the procedure. Follow-up data[3] from the Edmonton group in subjects
undergoing islet transplantation show evidence of the following
complications in some subjects:

        Acute risks associated with the procedure (perioperative portal vein

        Portal vein thrombosis

        Elevated liver function tests

        Hypercholesterolemia requiring statin therapy


   It should be noted that the occurrence of the above phenomena in some
patients should not detract from the overall benefits of islet
transplantation in correcting labile glycemia in carefully selected

   On a more disconcerting note are the results from a clinical study by
Breay W. Paty, MD, Pacific Northwest Research Institute, Seattle,
Washington, and colleagues,[6] examining the counterregulatory response to
hypoglycemia in type 1 diabetic islet transplant recipients. It has been
previously observed that whole pancreas transplantation restores
hypoglycemia counterregulation in type 1 diabetes patients in long-term
follow up studies.[7] However, type 1 diabetic recipients of intrahepatic
islet transplants (Edmonton protocol) exhibited a different response. In
these patients, stepped hypoglycemic clamp studies revealed a blunted
glucagon and epinephrine response to induced hypoglycemia compared with
nondiabetic controls. In addition, hypoglycemia symptom scores were
attenuated in the islet recipients compared with controls.

   The nature of the defect contributing to the impaired counterregulation
in the islet recipients is unclear. These results raise a note of caution in
patients who may require exogenous insulin supplementation
posttransplantation, since they are at a greater risk for hypoglycemia. In
animal studies, islets implanted intraperitoneally or under the kidney
capsule exhibited preserved glucagon responses, whereas intrahepatic islets
showed an impaired response. Thus, these findings raise questions about the
suitability of the liver as an implantation site for islets.

   The Future of Islet Transplantation

   Continued scientific progress in the areas of islet isolation,
implantation, and graft protection have led to greater success in clinical
application of islet transplantation. A major barrier to widespread use of
this procedure is the shortage of donor tissue. As alternate sources are
developed, such as animal sources (xenotransplantation) and engineered islet
cells and stem cells, islet transplantation may become a viable therapeutic
option. The promise of a cure for type 1 diabetes may well be realized.

   Summary: Implications for Clinical Practice

        Significant progress has been made in devising automated methods to
isolate purified human islets and increase the yield from a donor pancreas.

        Therapeutic strategies to prevent immune attack and promote survival
of islet grafts show promise.

        The Edmonton protocol is a minimally invasive procedure for
intrahepatic islet implantation that has resulted in highly successful
clinical outcomes of insulin independence in labile glycemic type 1 diabetes

        There is evidence that hypoglycemic counterregulatory responses may
be impaired in intrahepatic islet transplant recipients, and such patients
requiring exogenous insulin posttransplantation may be at risk for
hypoglycemic recurrence.

        The major obstacle to wide application of islet transplantation
remains the availability of donor tissue, although strategies for alternate
sources are in development.


      1.Ricordi C. Islet transplantation: a brave new world. Lilly Lecture.
Program and abstracts of the
        62nd Scientific Sessions of the American Diabetes Association; June
14-18, 2002; San
        Francisco, California. Diabetes, Volume 51, Supplement 2.
      2.Shapiro AMJ, Lakey JRT, Ryan EA. Islet transplantation in seven
patients with type 1 diabetes
        mellitus using a glucocorticoid-free immunosuppressive regimen. N
Engl J Med.
      3.Ryan EA, Lakey JR, Paty BW, et al. Clinical follow up after islet
transplantation. Program and
        abstracts of the 62nd Scientific Sessions of the American Diabetes
Association; June 14-18,
        2002; San Francisco, California. Abstract 131-OR. Diabetes, Volume
51, Supplement 2.
      4.Yang Z, Chen M, Fialkow LB, et al. Suppression of autoimmune damage
to transplanted islets in
        NOD mice by using the novel anti-inflammatory agent lisofylline.
Program and abstracts of the
        62nd Scientific Sessions of the American Diabetes Association; June
14-18, 2002; San
        Francisco, California. Abstract 42-OR. Diabetes, Volume 51,
Supplement 2.
      5.Plesner A, Korneluk RG, Liston P, et al. The X-linked inhibitor of
apoptosis protein (XIAP) protects
        transformed beta cells from cytokine-mediated killing and prolongs
murine islet allograft survival.
        Program and abstracts of the 62nd Scientific Sessions of the
American Diabetes Association;
        June 14-18, 2002; San Francisco, California. Abstract 41-OR.
Diabetes, Volume 51, Supplement
      6.Paty BW, Ryan EA, Lakey JR, et al. Intrahepatic islet
transplantation fails to restore hypoglycemic
        hormonal counterregulation and symptom recognition in
insulin-independent transplant
        recipients. Program and abstracts of the 62nd Scientific Sessions
of the American Diabetes
        Association; June 14-18, 2002; San Francisco, California. Abstract
37-OR. Diabetes, Volume 51,
        Supplement 2.
      7.Paty BW, Lanz K, Kendall DM, Sutherland DE, Robertson RP. Restored
        counterregulation is stable in successful pancreas transplant
recipients for up to 19 years after
        transplantation. Transplantation. 2001;72:1103-1107.
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