Activation/deactivation of macrophages and CD4+ T lymphocytes in experimental asthma

Abstract

Over the last 2 to 3 decades, the prevalence and severity of asthma and allergic disease has increased extensively in urban environments. The "hygiene hypothesis" was proposed in order to explain this increased incidence. This hypothesis is based on epidemiological evidence showing an inverse correlation between infections and allergic or autoimmune diseases. Recently, it was proposed that infections generate regulatory T cells that inhibit allergic (Th2) or autoimmune (Th1) diseases. Accordingly, the control of infectious diseases in urban environments decreased Treg cells activities that lead to a deregulated immune system. Various Treg cells has been characterized, natural Treg (CD4+ CD25+ CD45RB low) which inhibit aureactive T cells and adaptive Treg, that inhibit Th1- or Th2-mediated immune reactions. The adaptive Treg are heterogeneous cell population, but ali are CD4+ CD25+ and the majority expresses the transcription facto r Foxp3. One objective of the project is to investigate whether Treg induced by oral or nasal tolerance, or by recombinant BCG infection, or LPS would suppress the development of asthma. Another possibility for the suppression of asthma by infections is the emergence of activated macrophages. Recently, we have shown that i.v. administration of LPS suppresses established asthma. The suppressive activity was dependent on TLR4 and NOS2 expression and NO production. It is possible that other metabolites produced by activated macrophages such as those derived from indolamine, 2,3 dioxigenase or hemeoxigenase 1 pathways may also suppress asthma. For this purpose we will test some classical TLRs agonists (PIC, LPS or rBCG), or a synthetic TLR4-agonist on the development of asthma with focus on these metabolic pathway. (AU)