Controlling allergen-specific Th2-type responses by targeting DC surface lectins (PI: Oh, SangKon) Increasing numbers of patients with allergic diseases demand safe and long-term effective therapeutics. Allergen-induced pathogenic immune responses are the major cause of multiple types of allergic diseases, including allergic atopy, dermatitis, allergic rhinitis, and allergic asthma. The pathophysiology of such allergic immune disorders is complex and is often associated with several factors (e.g., genetic susceptibility, age, and route and dose of allergen exposure). However, studies in the past have revealed that allergen-specific Th2-type immune responses are directly associated with the development of such allergen-induced immune disorders. Therefore, therapeutic approaches with immune modifiers of the Th2 pathway represent a rational strategy for the treatment of such allergic diseases. However, current strategies targeting individual effector molecules (e.g., receptor antagonists and soluble receptors as well as neutralizing monoclonal antibodies (mAbs) to Th2 cytokines) may be insufficient to resolve the complex and multiple-effector-driven allergic immune disorders. Although specific immunotherapy (SIT) has been a hallmark of care among allergists for decades, considerable controversy still remains regarding its clinical efficacy, period of treatment, and socioeconomic consequences. We have recently found that human dendritic cells (DCs;the major immune inducers and controllers) activated via Dectin-1 with components of bacterial cell wall can significantly down-regulate Th2-type immune responses in our in vitro experiments using peripheral blood mononuclear cells from allergic patients. Thus, we surmise that activation of patient DCs via Dectin-1 can effectively control the pathogenic Th2-type immune responses in patients. This strategy targets Th2-type T cells, and thus it is expected to be more efficient than blocking one or two effector molecules secreted from the pathogenic Th2-type T cells. Furthermore, our immunotherapeutic strategy could bring long-term effects by reprogramming the quality of the pathogenic Th2-type T cells toward other cell types. To develop a novel human immunotherapeutic for such allergic immune disorders, we have generated an agonistic anti-human Dectin-1 mAb which cross-reacts with Dectin-1 in non-human primates (NHP). In this study, we propose to test the effectiveness of anti-hDectin-1 mAb in controlling Th2-type T cell responses followed by decreased IgE responses in both human in vitro (in Aim 1) and NHP in vivo (in Aim 2) using patient PBMCs and an NHP model of allergic atopy, respectively. At the end of this exploratory study (R21), we will be able to determine: The effectiveness of anti-hDectin-1 mAb treatment in human in vitro and NHP in vivo. This will lead us 1) to further study the effectiveness of anti-hDectin-1 mAb in broader ranges of allergic diseases, 2) to humanize anti-hDectin-1 mAb for toxicity and clinical studies in the near future, and 3) to design new and effective vaccine strategies that can bring long-term benefits to many allergic patients in the near future.
Increasing numbers of patients with Th2-driven allergic diseases highly demands effective therapeutics. This work tests a novel immunotherapeutic strategy that can control pathogenic Th2-type immune responses by targeting receptors expressed on major immune inducers and controllers, e.g. dendritic cells. The results of this study will have immediate implications for the rational design and development of effective immunotherapeutic and vaccines for several types of allergen-induced immune disorders. 1
|Duluc, Dorothée; Joo, HyeMee; Ni, Ling et al. (2014) Induction and activation of human Th17 by targeting antigens to dendritic cells via dectin-1. J Immunol 192:5776-88|