Type 1 Diabetes (T1D) is an auto-immune disease in which beta cells in the pancreas are killed by auto-reactive T-cells. Auto-reactive T-cells are activated by dendritic cells that present antigens... Show moreType 1 Diabetes (T1D) is an auto-immune disease in which beta cells in the pancreas are killed by auto-reactive T-cells. Auto-reactive T-cells are activated by dendritic cells that present antigens. Immunotherapy could reverse T1D, however. A case report of a T1D patient showed that after intravenous immunoglobulin treatment her insulin needs dropped completely. Similarly, the majority of T1D patients were insulin independent after autologous hematopoietic stem cell transplantation. As these therapies only showed incidental success or are a drastic reset of the immune system, respectively, other milder therapies were studied as well. Autologous tolerogenic dendritic cell therapy, for instance, is a reproducible, stable therapy and does not differ between T1D patients and healthy subjects. In addition, the author described that when mesenchymal stromal cells were activated, they were able to suppress an antigen-specific immune response, thereby potentiating them as an antigen-specific therapy besides their natural immunosuppressive nature. Activated mesenchymal stromal cells could also improve the islet of Langerhans’ microenvironment, as they secreted immunosuppressive and angiogenic factors. To conclude, the future of T1D therapies lies in finding a balance between suppressing the immune system and antigen-specific therapies combined with therapies that increase the vitality of beta cells. Show less
Identification of the cellular mechanisms involved in the occurrence and persistence of autoreactive lymphocytes is key for understanding T1D etiology. Comparing autoreactive T lymphocytes from... Show moreIdentification of the cellular mechanisms involved in the occurrence and persistence of autoreactive lymphocytes is key for understanding T1D etiology. Comparing autoreactive T lymphocytes from healthy individuals and T1D patients can provide clues as to what the driving force is for the destruction of β-cells and might designate potential targets for (immune) intervention. Elucidating in what way T1D associated gene variants actually contribute to disease development, i.e. understanding the functional aspects of genetic risk, and how genetic control of autoantigens influences autoimmunity may provide crucial clues to the clarification of the enigma of T1D. This thesis aims to answer several of these issues by investigating the role of transcriptional and post-transcriptional gene control in T1D. Show less
In this thesis, in close collaboration with my research colleagues, I have shown that T-cell recruitment in both spontaneous autoimmune diabetes and islet transplantation requires presence... Show more In this thesis, in close collaboration with my research colleagues, I have shown that T-cell recruitment in both spontaneous autoimmune diabetes and islet transplantation requires presence of a cognate antigen, which could be used as an argument in favour of further pursuing antigen-specific therapies. We have shown that recurrent diabetes in an islet transplantation model is driven by memory auto reactive T-cells and this latter finding has contributed to the present testing of immune suppressive drugs that indeed address recurrent autoimmunity, to improve outcome in clinical islet transplantation. We have designed and tested a novel auto-immune diabetes cell line tracing model for future testing of the regenerative capacity of islet-cells. We have shown that immune evasion protects beta-cells from autoimmune T-cell attack in vivo. Currently different immune evasion techniques, such as islet encapsulation are being tested in the clinic. We have shown that recall immunity is preserved in spite of high dose anti-CD3 treatment, adding to the safety of high dose anti-CD3 treatment as an immune modulator agent in the treatment of T1DM. Show less
