Biomedical Sciences and Engineering MS Thesis Defense by Dilem Ceren Oran

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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

BIOMEDICAL SCIENCES AND ENGINEERING

MS THESIS DEFENSE BY DILEM CEREN ORAN

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Title: Design of Local Immune-Privileged Microenvironment to Prevent Islet Graft Rejection

Speaker: Dilem Ceren Oran

Time: August 18, 2017, 10:00

Place: ENG 127

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Assoc. Prof. Seda Kızılel (Advisor, Koc University)

Assist. Prof. Cem Albayrak (Koc University)

Prof. Duygu Avcı Semiz (Boğaziçi University)

Abstract:

The development of tolerance induction approaches via immune engineering that can restore and/or replace non-functional tissues and organs represents the leading front of emerging regenerative therapies. Type-1 diabetes (T1D) is an organ-specific autoimmune disease characterized by destruction of pancreatic β cells, which are insulin-secreting cells by autoreactive T cells and other immune cells. Loss of β-cell, thus insulin, makes patients dependent to the exogenous insulin or to overcome this need; transplantation of pancreas or intact islets. One of the promising approaches used for treatment of diabetes is transplantation of islets; however, it also comes with its pitfalls. First and most obvious one is the limitation of donor source. In addition, transplantation of islets or pancreas requires suppression of immune system to prevent graft rejection. This suppression is achieved through immune suppressor drugs, which leaves the body defenseless against infections and even more susceptibility to other complications such as cancer. Considering all these limitations, immunotherapeutic strategies have focused on restoring immunologic self-tolerance, thus removing the problem at it roots; preventing β cell destruction by patients’s own immune system. The main focus of this approach is regulatory T cells (Tregs), which are essential cells in suppression of autoreactive immune responses and maintenance of self-tolerance. Stellate cells (SCs) have various effects on immune system such as recruitment of Tregs and induction of T cell apoptosis. Besides, they can promote vascularization, secreting vascular endothelium growth factor (VEGF). Some chemokines are also key modulators in recruitment of Tregs. Macrophage-derived chemokine or CC chemokine 22 (MDC/CCL22) is one of the novel chemokines used for Treg recruitment by binding to CCR4 receptor on their membrane. In this study, we designed an immune privileged microenvironment around implantable insulin secreting islets to provide local graft tolerance and to overcome limitations associated with donor cells. We focused on achieving local immunosuppression through overexpression of CCL22 proteins by SCs which recruited immunosuppressive Tregs. We prepared insulin-secreting pseudoislets through aggregation of mouse insulinoma 6 (MIN6) cells as a model system to mimic naïve islet morphology. Our results demonstrated that transfected SCs can secrete CCL22 and recruit regulatory T cell population towards the implant in vivo. This study is promising to provide fundamental understanding of the SC-islet interaction, ligand synthesis and transport from stellate cells at the graft site for ensuring local immune tolerance to target T1D. Our results also establish a new paradigm for creating tolerable grafts for other chronic diseases such as diabetes, anemia, cancer, CNS diseases and advance the science of graft tolerance.