MODELLING CELL MEDIATED IMMUNE RESPONSES IN THE COMPUTER

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DESCRIPTION (provided by the applicant): Computational modeling, if properly used, is a valuable way to unravel and comprehend the complexity of the Immune System, which - if an understatement is allowed - has not grown any simpler since a decade ago, when we began the construction of IMMSIM. Today, with our motivation intact, and our codes more sophisticated, we want to show the results obtained with a more complete immune system in machina. This proposal describes continuing efforts for the next three years intended to capture the full potential of a model that is now able to reproduce many kinds of engagement of the immune defense. The decisive step in this ambitious program was to construct the "cellular" branch of immunity and to splice it on to the original humoral response model, a deed accomplished under the current NIH grant R0lAI042262. The test target was infection by virus, since it is known that the work of both T effector cells and antibodies is required to conquer the infection. By using a large diversity of viruses we determined the weight of their behavioral parameters for the fate of the infected organism, and saw that the relative merit of the two responses was different from case to case, and was also dictated by the makeup of the virus. As an emergent finding, we discovered that humoral and cellular branches are often in competition and thwart each other during the response. Over the next three years, the following aims will be pursued: a) complete the array of diverse behavioral parameters of the virus and investigate their effect on the defense strategies of the infected organism; b) investigate the effect of virus mutation during infection and the countermoves of the immune system; and c) determine the impact of immunogenicity gaps between primary and secondary stimulation (e.g., between vaccine and invader) in order to suggest, eventually, guidelines for vaccine design.