Name of Student:
Malihe Sadat Poormasjedi Meibod
Research Supervisor: Dr. Aziz Ghahary
Title of Presentation: Suppression of Islet Xenogeneic Immune Responses by Indoleamine 2, 3
Dioxygense Expression
Abstract
Background: Type 1 diabetes (T1D) is characterized by destruction of pancreatic β cells
which results in severe medical complications. Successful islet transplantation trials rising
hope that islet transplant would become a new therapeutic approach for treating T1D.
Unfortunately, in many cases complications arising from graft rejection or anti-rejection
medication have limited the absolute success of transplantation as the treatment of choice.
One of the primary complications of transplantation is the necessity for lifelong, systemic
immunosuppression. To address this concern, our research group developed a novel local
immunosuppressive therapy based on Indoleamine 2, 3 Dioxygense (IDO) expression that
prevents islet allograft immune rejection. IDO, catalyzing tryptophan to N-formylkynurenine,
is mainly involved in peripheral tolerance induction by suppressing adaptive immune
responses.
To further complicate efforts of organ donation, human organ shortages have fueled the
concept of xeno-organ transplantation. In spite of several attempts during last decade to
develop an effective immunosuppressive therapy, delayed xenograft rejection, mediated by
progressive macrophage infiltration, is still the main issue preventing the widespread usage of
animal organs for transplantation.
Hypothesis: Local IDO expression can prevent islet xenograft immuno-rejection via
modulation of macrophage inflammatory responses and inducing apoptosis in these cells.
Methods: For in vivo studies composite three-dimensional islet grafts were engineered by
embedding xenogeneic rat islets within the normal or IDO–expressing fibroblasts populated
collagen gel matrix. These grafts were then transplanted into renal subcapsular space of mice.
Macrophage infiltration and xenogeneic islet transplant uptake were determined in the graft
recipient mice. For in vitro studies, Raw264.7 cells (leukaemic macrophage cell line), were
cultured in tryptophan deficient media with increasing concentrations of kynurenine.
Raw264.7 cells viability in different conditions and their nitric oxide production in response to
Lipopolysaccharide (LPS) stimulation were evaluated.
Results: In vivo studies showed that macrophage infiltration was significantly reduced in
IDO-expressing grafts without administration of systemic immunosuppressive agents. Islet
structure and functionality remained intact in IDO-expressing grafts while macrophages
infiltrated and destroyed islets in control mice. In vitro studies show that tryptophan deficiency
but not kynurenine enriched environment has significant inhibitory effect on the nitric oxide
production by Raw264.7 cells. In addition, it was shown that tryptophan deficiency but not
high levels of kynurenine reduce Raw264.7 cells viability by activating apoptosis in these
cells.
Conclusions: Findings of this study supports the feasibility of using local IDO expression as
an alternative for systemic immunosuppressive treatments for protecting islet
xenotransplantation.