Strategies to improve macroencapsulated islet graft survival
- Publisher: Karolinska Institutet, Department of Clinical Sciences
MEDICIN OCH HÄLSOVETENSKAP | MEDICAL AND HEALTH SCIENCES
mesheuropmc: endocrine system
Chronic immunosuppressive therapy may have severe side-effects. In cell
transplantation, the graft can be encapsulated within a membrane chamber,
providing a physical barrier against the immune system. The cell graft
then becomes dependent on the diffusion of nutrients and oxygen from the
surrounding microcirculation. A major drawback has been the formation of
avascular fibrotic tissue around the chamber. The immunoprotective device
studied (TheraCyte ) has an outer membrane inducing neovascularization.
However, major parts of the encapsulated graft are still lost soon after
transplantation, probably because of relative hypoxia and malnutrition.
The overall aim of this thesis was to assess various strategies to
improve islet graft survival in the device, using rodent models.
The purpose of the first paper was to improve the method for histological
evaluation of the vascularization around the device. Vascular profiles
within various distances from the membrane surface were counted at
different times and then correlated with glucose kinetics. We found that
the vascular profiles within 100 ìm had the highest correlations with
glucose kinetics and concluded that vessels within this distance are
important for the exchange of small molecules between the circulation and
the device s lumen. Therefore, we recommend that 100 ìm should be used in
histological evaluations of the membrane vascularization.
In the second paper we hypothesized that preimplantation of the device
should improve encapsulated islet graft survival. Previous studies have
indicated that it takes up to 3 months for recovery of the
microcirculation after membrane implantation. Therefore, we implanted
empty devices and transplanted islets 3 months later in these chambers.
This approach significantly improved the cure rates of diabetic animals,
and the islet dose required for cure was reduced by about 10 times.
Morphometry evaluations confirmed increased graft survival in
The third paper aimed at evaluating the effects of exendin-4 treatment on
the metabolic outcome after islet transplantation. Exendin-4 inhibits
islet apoptosis, stimulates islet differentiation and regeneration and
has beneficial effects on peripheral tissues. We found that exendin-4
treatment significantly improved the metabolic outcome after free islet
transplantation to the renal subcapsular site. The benefit lasted longer
than the treatment, suggesting that exendin-4 had long-standing effects
on the islet graft. This substance seems to be an interesting new
approach to improve the survival also of encapsulated islet grafts.
In the last paper we evaluated the risk of recipient sensitization using
macroencapsulated islets. A heterotopic heart graft was transplanted one
month after free or encapsulated islet transplantation. The
time-to-rejection was significantly shorter in the free islet group,
while it did not differ between encapsulated islet graft recipients and
naive animals. We therefore conclude that the device protects against
sensitization, at least during the first month after transplantation.
Today, side-effects of the immunosuppressive therapy are one of the main
limiting factors for the use of islet transplantation. If
immunoprotection could be achieved by encapsulation of the islet graft,
it should be possible to widen the indications. This thesis describes
promising strategies to improve the survival of macroencapsulated islet
grafts, which might contribute to make macroencapsulation a clinical