Modulatio of polarized immune responses in immunologically or genetically manipulated animals

Abstract

Proper functioning of the immune system depends on cytokines and on cell-to-cell interactions that are mediated by adhesion and co-stimulatory molecules. Cell-to-cell contact is fundamental for lymphocyte activation. However, cytokines are essential for further differentiation of lymphocytes and for the activation of non lymphoid cells such as macrophages. Convincing evidence has accumulated over the past years for the existence of polarized immune responses governed by subsets of CD4+ helper T lymphocytes. It was showed that mouse CD4+ cell clones could be distinguished by their pattern of cytokine secretion. They termed Th1 cells as T cells that produce IL-2, TNF- and the macrophage-activating cytokine (IFN) and Th2 cells as those that produce IL-4, IL-5, IL-6 and IL-13. It soon became clear that Th2-dominated responses were associated with allergic reactions whereas Th1 dominated responses were associated with delayed type hypersensitivity reaction, macrophage activation, and resistance to infection by intracellular parasites. Certainly the Th1/Th2 paradigm is an oversimplification of the complex cellular interactions that operate in the immune system. However it accommodate and synthesize, at least, two major immunological reaction mediated by T cells, namely the delayed-type of hypersensitivity (DTH) and the late phase reaction (LPR) of immediate-type hypersensitivity. Much of our understanding of the molecular mechanisms responsible for Th1 or Th2 polarization came from studies with animals with defined genetic background, or studies that utilized monoclonal antibodies against key cells or cytokines or studies that utilized genetically manipulated animals (KO animals that lack key elements of the immune system). Our proposal is to combine these types of approach to study the following immune reactions that are: 1) dominated by Th2 cells which are associated with generation of allergic responses that occur experimental asthma. We will specially focus on the induction of tolerance (oral or nasal) to asthma; 2) dominated by Th1 cells that are probably involved in macrophage activation induced by microorganisms, lectins and superantigens and in experimental Chagas' disease myocarditis. (AU)