The immune response to antigen is characterized by an initial activation followed by the development of effector mechanisms, such as the delayed-type hypersensitivity (DTH) in the murine system, and can be distinguished on the basis of lymphokine secretion. The Thl cells secrete IL-2, IFN-gamma and lymphotoxin and provide help for the DTH response whereas Th2 cells secrete IL-4, IL-5, IL-6 and IL-l0 and provide help for antigen-specific antibody responses. In vitro studies have revealed that the interactions occurring between these cells can be either antagonistic or synergistic. In vivo, the balance between these two subsets is tightly regulated, but when this regulation is not maintained, one subset may predominate over the other. This may be occurring in such diseases as asthma or systemic lupus erythematosus in which the Th2 cells have been shown to dominate.
The specific aims of this proposal are to use the mathematical tools of dynamic modeling to study the interactions between Thl, Th2 cells and the lymphokines they secrete. A model will be developed on the basis of available data. This model will be refined and precised using Thl and Th2 clones available in the laboratory. The model will then be analyzed for its dynamical content using a computer program. This involves allowing the variables to evolve over time, and points of equilibrium will be identified. These equilibria will correspond to normal states of balance between the two types of cells as well as abnormal states, reflecting certain disease states. An in vitro system will be developed to test the predictions of the model. This system will involve the use of a panel of antigen-specific T cell clones, some of which are Thl and others are Th2. These clones can be activated using the same antigenic stimuli. It will be possible, therefore, to carry out experiments in which Thl and Th2 clones of the same specificity are mixed, activated simultaneously, and the pattern of lymphokine secretion observed. It is anticipated that this approach will greatly increase their understanding of how these two cell types might interact in vivo, and ultimately could lead to possible therapeutic manipulations in diseases characterized by an imbalance between these two important T cell subsets.
