T helper cells (Th) play a central role in immune responses and are required for induction of cytotoxic T cell and most B cell responses. After antigen exposure, Th differentiate into characteristic stable phenotypes. Th1 cells secrete IL2 and gamma interferon, and promote IgG2a antibody secretion. Th2 cells secrete IL4 and promote IgG1 and IgE secretion. Two major projects have focused on characterizing and interfering with pathogenic Th responses. 1. Allergies, such as asthma, hay fever, and food allergies are mediated by IgE, which requires IL4, a Th2 product for its induction. Mice injected with ovalbumin/alum develop ovalbumin-specific IgE responses. I have shown that pretreatment of mice with killed Brucella abortus (BA; BA induces a Th1 response in systems where B cells are polyclonally activated) prevents IgG1 and IgE responses, while enhancing IgG2a responses. My RNA studies show that BA induces IL12 and gamma interferon, thus creating a milieu favorable to initiation of Th1 responses. Most importantly, established IgE responses can be downregulated with BA-ovalbumin conjugates. Preliminary evidence suggests that emergence of previously silenced Th1 cells is responsible for this phenomena. Future work will concentrate on mechanisms by which BA redirects Th responses in allergy, using ovalbumin TCR-specific transgenic mice. 2. Experimental Allergic Encephalomyelitis (EAE) is a multiple sclerosis-like disease in mice mediated by myelin basic protein-specific Th1 type cells. Recently, we have shown that (i) IL4 given in vivo attenuates EAE by downregulating Th1 cytokines in the brain, and promoting Th2 cell expansion peripherally, and (ii) retinoids favorably affect the course of EAE by inducing Th2 MBP-specific cells; this effect is seen even after initiation of disease by Th1 cells. Ongoing work includes (i) determining the role of costimulatory molecules in prevention of EAE, and specificity of costimulatory molecules for inducing a Th1 vs. Th2 response, and (ii) exploring our recent discovery that IL4 mRNA is naturally present in large amounts in brains of young mice, which are resistant to EAE.
