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Lay Summary
Immune tolerance is the "holy grail". It is the situation in which three conditions are all achieved:
There are hundreds of experimental reports describing the numerous intertwining molecular pathways involved in the induction of tolerance. Many of these pathways serve multiple functions, and many of the functions overlap across several pathways. Therefore the mechanisms by which immune tolerance is induced are complex and redundant, with many loopholes that foil attempts to induce tolerance in humans.
Research Objective
Potential Impact on Health
Design
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Background
The human immune system is in a constant balancing act: it must recognize and destroy disease-causing foreign cells and organisms, without attacking the host's (self) cells. When the immune system's balance is disrupted, autoimmune diseases emerge, such as diabetes mellitus, inflammatory bowel disease (Crohn's and colitis), systemic lupus erythematosis (SLE), and rheumatoid arthritis. Patients with autoimmune diseases often require long-term treatment with immune suppressing medications. Furthermore, anyone requiring an organ transplant such as a kidney, liver, lung or heart must receive daily immune suppressing medications to prevent the immune system from attacking the organ. Long-term suppression of the immune system makes these patients susceptible to infections and cancers, which can be life threatening.
The objective of this project is to capture all the information in the medical literature that pertains to immune tolerance mechanisms, and to build a computer simulation that can keep track of all that information so that immune tolerance researchers can test their hypotheses regarding induction of immune tolerance, prior to experimenting in humans. The rationale is that even the smartest immunologist cannot simultaneously visualize all current information on immune tolerance, and therefore important relationships and potentially successful approaches are being missed.
Within 2 years this project will empower researchers to discover effective immune tolerance therapies sooner, more efficiently, and with a lower burden on clinical trial patients since ineffective approaches may be weeded out prior to their use in clinical trials. The immune tolerance simulator will provide an overarching perspective of immune tolerance mechanisms, and will allow researchers to explore this complex network of information in real time. For example, a researcher studying kidney transplants may be interested in blocking 3 specific pathways involved in the immune response, based on information she has read in 20 publications. If she first tries her approach on the simulator, she may find that two other pathways circumvent her blocked pathways, and result in rejection of the organ. The simulator would inform her as to what these two pathways are, and would provide the relevant references to her so that she could read about those additional pathways, rethink her approach, and retry her new approach on the simulator.
The "blueprint" of the simulator and the necessary software components are complete. The technical aspects of the simulator are summarized here: Technical Summary. The next step is to "teach" the model by populating it with the information in the literature. There are approximately 100 new relevant publications each year. The simulator will be a freely accessible, user-friendly program on the Internet.
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