Title: Developmental pathway of IgE-secreting plasma cells: prospective targets for the treatment of asthma
Funder: Asthma UK

Abstract: Because of its central role in allergic disease and in asthma, immunoglobulin E (IgE) is a favoured target for drugs capable of treating or preventing attacks. The options currently available all seek to block the action of the existing IgE. The relief afforded by all such methods is by their nature transitory, since the pool of IgE is quickly replenished. Therefore a far more effective measure would be ablation of the specific IgE-producing cells or their precursors. Thus far technical difficulties have prevented the attainment of this objective. Our proposal is predicated on strong indications that the difficulties can now be overcome and hence the ablation of IgE-secreting plasma cells would be an ideal strategy for the treatment of asthma and may potentially cure the disease. Our objective in this project is to devise an effective strategy to kill these cells or to prevent their development from precursor cells. The main obstacle to elucidation of the developmental pathway leading to the formation of plasma cells has been the exceedingly low concentration of IgE-expressing B cells in the circulation, even though, as we have shown, they are abundant in the target organs of allergic disease. Three other research groups have developed transgenic mice expressing tagged IgE, but these have given contradictory and ambiguous results. We are among the few focusing on IgE regulation in human (as opposed to mouse) B cells. We have recently developed the means to induce generation of IgE-secreting plasma cells from purified human B cells in vitro in high yield. We are also now able to purify native IgE-secreting plasma cells from nasal polyps, biopsies from the bronchial mucosa and bone marrow. These tissues provide the survival niches for IgE;producing cells in vivo. The new procedures will allow us to characterize the cells and define their properties at different stages of development. Moreover, we can manipulate the cells of interest for the purpose of testing possible killing strategies, or uncovering new targets for intervention in asthma. One promising strategy is the use of new antibodies that bind selectively to membrane-associated IgE on the surface of the precursor cells: we have shown that these antibodies kill the cells in the test tube. We will isolate the IgE-secreting plasma cells from the tissues (nasal and bronchial mucosa and bone marrow), which are presumed to constitute their survival niches in vivo. We will quantify the relative levels of expression of membrane IgE on these cells and determine their susceptibility to killing with the antibodies against this IgE.We shall undertake, furthermore, a genome-wide analysis of protein expression in the cells at different developmental stages, with a view to identifying prospective drug targets along the pathway. We will analyze protein networks involved in the surveillance for DNA damage, DNA repair, apoptosis and cell division, as in our earlier work. During this project we would take at least the essential preliminary steps to validate the targets chosen out of these networks as the basis for future development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY;INFLAMMATORY AND IMMUNE SYSTEM