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 Investigators:
Mark Atkinson, Terrence
Flotte
One strategy for prevention of type I diabetes is
that of islet transplantation, which for patients with the disease,
I is an appealing approach to replacement of insulin-secreting tissue.
Advances in transplantation in many fields have shown success rates
of 85 to 70% at one to five years, respectively. However, to date,
discontinuation of insulin therapy for more than a year is relatively
infrequent following islet transplantation in type I diabetes. The
reasons for these disappointing results are many. The same drugs
(e.g., cyclosporin, FK506) that are so successful at bringing organ
transplantation to a relatively common practice are also (unfortunately)
unfavorable to the conditions within the body necessary for islets
to function. In addition, immune responses against islets both in
terms of those normally associated with organ transplantation as
well as a recurrence of the autoimmune (anti-self) responses that
initially provoked the formation of diabetes to begin with, constitute
major obstacles to successful treatment of transplantation in type
I diabetes. Therefore, successful clinical islet transplantation
will require new and creative avenues of therapy to inhibit both
the immune responses to the grafted islets and the autoimmune response
that destroys recipient pancreatic islet cells.
Diabetes investigators have discovered that administration
of natural occurring immune system compounds known collectively
as "cytokines" posses the ability to inhibit immune responses and
protect NOD mice from not only diabetes, but in addition, allow
transplanted islet cells to function. The mechanisms of how this
occurs are still at the hypothesis stage, but it would appear that
the cytokine IL-4 accomplishes this by restoring the normal growth
and function of T cells that mediate protection from type I diabetes.
A second cytokine, IL-10, may act by diminishing the function of
cells responsible for destruction. Our investigations win test whether
IL-4 or IL-10 can be used in conjunction with islet transplantation
to enhance and prolong the survival of grafted islets. This will
be studied using a gene therapy approach, which has been reported
to offer a potentially effective treatment for various inherited
diseases.
The concept of cytokine gene therapy for islet cell
transplantation in type I diabetes is not new. It has been previously
investigated in some model systems with various degrees of success;
some working while others have not. However, most viral gene delivery
systems utilized to date have demonstrated significant limitations
in practicality due to the level and duration of recombinant transgene
expression as well as their induction of host immune to viral or
therapeutic proteins. We have developed a series of adeno-associated
virus vectors carrying cytokine genes which when infected into islet
cells or mouse muscle cells, they demonstrate stable high-level
expression of cytokines.
The objective of this proposal is to establish a method
affording the prevention of type I diabetes in cases of islet cell
transplantation for the reversal of the disease. We will test the
hypothesis that type I diabetes can be prevented in NOD mice through
the use of adeno-associated virus transfer of IL-4 and IL-I0. In
this approach, the IL-4 or IL-IO cytokine genes (alone or in combination
with other the cytokine gene) will be inserted into adeno-associated
virus. This virus carrying the cytokine gene will be used to infect
islet cells or injected into the muscle prior to transplantation
with the belief that this process will allow for the infected cells
to produce the immune system altering cytokines. We will determine
whether the immune responses that generally follow islet transplantation
can be diminished or inhibited by the IL-4 and IL-10 cytokine gene
therapy, and whether this results in the long term prevention/cure
of type I diabetes. If proven safe and effective, we would hope
these studies allow for quick translation from a method for cure
in animals to a means of finding a cure for diabetes in humans.
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