Type 1 diabetes : the autoimmune process and islet transplantation

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the selective loss of the insulin-producing β-cells residing in the islets of Langerhans in the pancreas. Cytokines are involved in diabetes development in the nonobese diabetic (NOD) mouse model. NOD mice over-expressing the suppressor of cytokine signaling (SOCS-1) specifically in the β-cells are protected from T1D. Previous studies showed that immune cells infiltrated the pancreas of SOCS-1-transgenic (tg) mice, however, infiltrating T cells were less pathogenic than those infiltrating the islets in non-tg NOD mice. In this thesis one of the aims was to further dissect the infiltrating T cell populations in SOCS-1-tg mice in order to gain further insight into the mechanisms behind disease protection. In paper I the main finding was that specific autoreactive T cells were strongly reduced in the pancreas of SOCS-1-tg mice compared to non-tg mice. Previous studies have shown that autoreactive T cells are recruited to the pancreas by cytokine-induced CXCL10 expression by the islets. The receptor for CXCL10 is CXCR3, which was more frequently expressed on autoreactive T cells than bulk T cells. Since SOCS-1-tg mice have reduced expression of CXCL10, autoreactive T cells are less likely to migrate to the pancreas of these mice and pose one possible explanation for this finding. This study shows that the β-cell response to cytokines plays a major role in the accumulation of autoreactive T cells to the pancreas.

Blood glucose metabolism in patients with T1D can only be restored by islet transplantation. Unfortunately, the benefits of islet transplantation are only short-term since the graft is lost over time. Therefore, exposing T1D patients to the risks associated with the immunosuppressive therapy cannot be motivated in most cases. In the second part of this thesis the aim was to evaluate new methods to prevent islet allograft rejection. In paper II it was shown that the mesenchymal stromal cell (MSC)-line MBA-1 suppressed T cell proliferation in vitro and slowed down rejection of allogeneic islets in Balb/c mice. This indicates the possible use of MSCs as cell therapy in islet transplantation. Another method to avoid immunosuppressive treatment is to encapsulate the islet allografts inside immunoprotective membranes (TheraCyteTM devices) preventing immune cells from interacting with the grafts. In paper III it was shown that the TheraCyteTM device completely protected islet allografts from rejection in both naive and immunized recipient rats. This is an important finding since many patients are sensitized prior to transplantation for example due to a previous transplant. Finally, graft loss is difficult to study in humans and small animal models do not always reflect the human situation. Therefore, the final aim of this thesis was to evaluate so-called humanized mice for their potential use to study human islet rejection mechanisms. In paper IV human immune system (HIS) mice were established and transplanted with human islets. However, no signs of rejection were detected in the HIS mice questioning the usefulness of this model as a tool to study human islet transplantation. This highlights the need for more robust humanized mouse models.