Preface - Ous-research.no

Cell Transplantation
Figure 3. Effects of glucocorticoids (GC) on insulin secretion.
emphasis on their influence on insulin metabolism in
human islets. The agents that are tested are cyclosporine A,
tacrolimus, rapamycin, daclizumab, mycophenolate mofetil,
FTY 720, LEA 29 and the glucocorticoid Solu-Medrol (Fig. 3).
Each drug is added to human islets in culture medium at
four different concentrations in order to establish the doseresponse
relationship. The effect on islets is analysed regarding
insulin secretion, expression of TF, MCP-1 and TNF-alfa,
mRNA content, and apoptotic genes (Siva (CD27BP), TNFR
1, TNFR2) at different time points after incubation. Specifically,
our data have shown that glucocorticoids induce a
marked reduction of TF mRNA levels which correlates to the
strength of IBMIR and subsequently, the success rate of islet
transplantation. Furthermore, the data show that a negative
influence of glucocorticoids on insulin secretion early
after incubation of human islets is completely reversed on
day 7 (see fig.). This suggests that brief exposure of glucocorticoids
to islets pretransplant suppresses IBMIR and aid
engraftment of transplanted islets.
Several other anti-inflammatory compounds have been
tested such as resolvin E1 and the LXR-agonist GW3965.
Currently, the effects of the IL-1β receptor antagonist
Anakinra and the anti-IL-6 receptor monoclonal antibody
Tocilizumab on islets are investigated. These studies are
defined in a PhD-project for dr. Afaf Sahraoui.
2.2 Whole-blood tubing loop system
Many of the immunosuppressive agents (e.g. calcineurine
inhibitors) are largely bound to erythrocytes in vivo. Due to
the IBMIR effect it has been shown that a large number of
transplanted islets rapidly are trapped in clots of erythrocytes
containing high concentrations of the immunosuppressive
drug. We have postulated that a slow release of the
drug to the islets will ensue. To test this slow-release effect,
islets (4000 IEQ) are suspended in 6 whole-blood tubing
loops (Fig. 4) and drugs are added to the loops at different
time points i.e. 0, 30, 60, 120 and 240 minutes
Figure 4. The whole-blood tubing loop system.
2.3. Intracellular regulation of immunosuppressive
drugs in human islets
Together with the i2mc research group, headed by Prof.
Stein Bergan we are investigate the pharmacokinetics, pharmacodynamics
and pharmacogenomics of the immunosuppressive
drugs in human islets.
Project 3. To explore and develop striated musculature
as an alternative site for islet transplantation
Intraportal transplantation of islets is the most common method
for islet allo- and auto transplantation. However, functional
and experimental studies suggest that a large part
of the intraportal transplanted islets are destroyed shortly
after infusion, due to islet-blood interactions. In addition, it
has been suggested that intrahepatic islets are exposed to
high concentrations of diabetogenic immunosuppressive
drugs, nutrients and gut hormones. This may lead to hyper
secretion of undiluted insulin into surrounding hepatocytes
and focal steatosis. Steatosis following islet transplantation
may cause islet lipotoxicity and eventually be a risk factor
for the development of adenomas in the liver.
Finally, due to procedural risks,
it has been difficult to obtain
the serial biopsies necessary for
characterization of islet engraftment
or rejection in the liver. For
these reasons, development of
an alternative site for islet transplantation
has been suggested to
be an important factor for further
progress in the field. Although
porcine islets could be an unlimi-
Figure 5. The musculature islet transplantation
site.
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