PI: Dr. Marion Pepper
Location: UW Immunology
The Development of Tolerizing Immunotherapies for Asthma
Allergen-specific immunotherapy (SIT) induces immune tolerance through the administration of repeated, increasing doses of the causative allergen and results in the long-lasting remission of disease symptoms. Multiple immune functions have been suggested to contribute to SIT-induced immune tolerance in both mice and humans including: the diminished secretion of Th2 cytokines, skewing of IgE to IgG4 expression, enhanced production of IL-10 and TGF-β by CD4+ T cells and recruitment of CD4+ CD25+ regulatory T cells. While SIT currently provides the only curative therapy for asthma and allergy-related disorders, it remains an impractical therapy as it requires long-term treatment, exposes patients to high risk of anaphylaxis and exhibits variable efficacy particularly in patients with allergic asthma. For example, the current protocol for treatment of allergy to House Dust Mite (HDM) allergens, the most common cause of allergic asthma, involves an initial series of 20-30 injections of HDM extract followed by additional “maintenance” injections for three years and is effective in only 30% of patients who undergo the therapy. Ideally, the mechanisms of immune tolerance invoked by SIT can be mimicked and optimized by biological modifiers including novel vaccine strategies.
Induction of peripheral tolerance to foreign antigens is often associated with the emergence or activation of regulatory T (Treg) cells that can suppress CD4+ effector cell function. Treg cells exert their suppressive effects by localizing to secondary lymphoid organs during the induction of the immune response and to peripheral tissues during the ongoing immune response. Although there is ample evidence suggesting that Treg cells play a role in the therapeutic effects of SIT, it is not clear what types of Treg cells emerge, what their origin is, what Th2 populations they suppress, if they are required for suppression and if so, the mechanisms that lead to immune tolerance. We have therefore developed a model system to study how SIT with the HDM protein Derp1, or its immunodominant peptide, induces immune tolerance in both humans and mice. Using this system, we will be able to visualize how HDM-tolerant Derp1-specific CD4+ populations function, the mechanisms underlying this process and the mediators of this suppression. We will concurrently use these findings to direct the development of nanoparticle-based tolerizing vaccines with David Baker’s lab. These studies will lead to the development of novel biotherapeutics that will efficiently suppress the asthmatic response.