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MODELLING INTERACTION BETWEEN CD8+ T CELLS AND BETA CELLS IN PATHOGENESIS OF TYPE 1 DIABETES
Title
MODELLING INTERACTION BETWEEN CD8+ T CELLS AND BETA CELLS IN PATHOGENESIS OF TYPE 1 DIABETES
Creator
Xu, Qian
Date
2016, 2016-12
Description
Diabetes is one of the prevalent diseases in the USA, which affects the lives of millions of people. In 2010 only, there was a total of 234...
Show moreDiabetes is one of the prevalent diseases in the USA, which affects the lives of millions of people. In 2010 only, there was a total of 234,051 deaths linked to diabetes in the USA. Research related to preclinical and clinical assays are always costly and time consuming. Modeling is a helpful method to reduce the cost of clinical experiments and accelerates the discovery and improvement of new therapies. This research is focused on the development of a high performance agent-based model simulating the pathogenesis of Type 1 diabetes mellitus in pancreas. The whole immune response takes place in three compartments, pancreatic lymph node, circulation, and pancreas. A significant part of the complex interactions leading to Type 1 diabetes takes place in the pancreatic tissue. Therefore, the focus was placed on the islets of Langerhans in the pancreas, and the interaction of CD8+ T cells and Beta cells were modeled. T cell behavior was incorporated as rules in this model such as activation, migration, proliferation, apoptosis, and cytotoxicity. Likewise Beta cell death and regeneration under the T cell attack were modeled. The model is able to capture the trends of T cell and Beta cell variations during the disease progression and portrays the role of CD8+ T cells in the process. It is expected that, with the addition of other immune system and pancreatic tissue components, the model will be a valuable tool for the planning of clinical studies.
M.S. in Biomedical Engineering, December 2016
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AGENT-BASED MODELING OF IMMUNE RESPONSE IN THE DEVELOPMENT OF TYPE 1 DIABETES
Title
AGENT-BASED MODELING OF IMMUNE RESPONSE IN THE DEVELOPMENT OF TYPE 1 DIABETES
Creator
Xu, Qian
Date
2020
Description
Diabetes is a chronic disease that affects a large number of people around the world and cause many co-morbidities ranging from cardiovascular...
Show moreDiabetes is a chronic disease that affects a large number of people around the world and cause many co-morbidities ranging from cardiovascular diseases, neuropathy, retinopathy and blindness and kidney failure. The economic burden induced by diabetes is not only caused by the wage loss and medical burden, but also with the cost of treatment of diabetes and co-morbidities caused by diabetes. Clinical research for treatment and cure of diabetes is costly. Computer modeling and simulation studies provide an economical alternative to conduct preliminary evaluation of new hypotheses and alternatives in new therapies. The most promising results obtained from simulations can then be investigates experimentally, improving the efficiency of experiments and clinical studies. This work focuses on the development of an agent-based model to describe the destruction of islets and β cells and the development of Type 1 diabetes. The whole process of inflammation related to diabetes takes place in pancreatic lymph node, circulation, and pancreatic tissue with islets. The infiltration to islets and insulin-producing β cell damage happens in the pancreatic tissue with islets; the lymphocytes activation and antigen presentation majorly happened in the pancreatic lymph node. Therefore, the model described activities taking place in the islets in the pancreatic tissue section and pancreatic lymph nodes, the interactions among T cells, α/β cells, antigen presentation cells and immunosuppression cells. Cell behavior was obtained from the literature that published experiment results and used to develop the rules followed by the agents representing various types of cells and their interactions. The agent-based model provides a framework to describe relationship between lymphocytes and β cell through the trends of cell variations in the inflammation and demonstrates the effects of these cells in the disease development. Two different systems, a mouse model and a human model have been developed. The simulation results with the mouse model indicate that the different types of regulatory cells play different roles in suppressing inflammation. Among them, the regulatory T cells play the most important role in suppressing inflammation, but the B regulatory cell conversion is the key to induce the cascade of regulatory cell generation in inflammatory environment when there are no regulatory cytokines in the environment. The simulation results with the human model are mostly similar with mouse model, however, their effect of potential therapies such as addition of Tregs did not do as well as that in mouse model. The treatment method might be adjusted by combining other cytokines or immunosuppression cells in human assays.
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