Filariae are insect-borne tissue-dwelling roundworms that are a major worldwide cause of disease. They cause a type 2 immune response characterized by eosinophilia, elevated serum levels of Ag-specific and polyclonal lgE, and increases in T-cell production of IL-4, IL-5, and IL-I 3. Over time, though, chronically infected patients develop a state of immune hyporesponsiveness, with decreased T - cell proliferation and cytokine production in response to filarial antigen. The long range goal of this ultimately downregulate type 2 immune responses. The central hypothesis to be tested is that basophils initially serve to amplify and reestablish type 2 immune responses towards filariae once Ag-specific IgE is present Testing of the central hypothesis will be performed by addressing two specific aims: I) whether IgE-mediated activation of basophils amplifies ongoing type 2 immure responses towards filarial infections, and 2) whether preexisting Ag-specific IgE can rapidly reestablish a type 2 immune response upon reinfection with filariae.
Aim I will be accomplished by evaluating type 2 responses induced by filarial infection in the presence and absence of IgE blockade, FcER1 -deficiency, and basophil depletion.
Aim 2 will be addressed by assessing the rapidity with which type 2 rosponses develop in response to filarial infection in mice sensitized with filaria-specific IgE or induced to produce filaria-specific lgE by either prior vaccination or infection. The filarial model of Litomosoides sigmodontis will be used in these studies because it is the only model of filarial infection in mice in which infective larvae develop into mature, sexually reproducing adults. Information gained from these studies has the potential to lead to advances in I) helminth vaccine development, 2) mechanisms of inducing immune modulation, and 3) prevention and treatment of allergy and asthma. of
PROJECT RELEVANCE The goal of this study is to better understand the body's immune response to worms that invade human tissues. Results may lead to better approaches for developing vaccines against worms and to new concepts for how to treat autoimmune and allergic diseases.
