- Mechanisms regulating cytokine/mediator release by IgE receptor-bearing cells
This laboratory during the last decade has focused on understanding the role human basophils and mast cells play in allergic reactions, as it relates not only to their secretion of potent inflammatory mediators (e.g. histamine and leukotriene C4), but also to their production of pro-inflammatory cytokines. Particular emphasis has been on studies investigating the parameters and mechanisms underlying the production of IL-4 and IL-13 by basophils, as these two cytokines are known to play a critical role in the pathogenesis of allergic disease. As a result, this laboratory has played a significant role in characterizing the basophil as a major source of these "Th2-like" cytokines, so named for their initial description in a subclass of T helper lymphocytes. We first demonstrated this response in vitro using basophils isolated from blood and under conditions involving IgE-dependent and IgE-independent activation. More recently, we have extended these observations to clinically relevant disease by showing that basophils infiltrating the airways following allergen challenge are also a primary source of these cytokines. Overall, the implications are that basophils, by secreting all of the major products linked to allergic inflammation (i.e. IL-4, IL-13, histamine and LTC4), orchestrate both immunomodulatory and effecter roles in allergic disease.
We have long utilized human cells rather than cell lines in order to address the parameters, signal transduction, and pharmacological aspects underlying clinically relevant basophil and mast cell responses. As a result, this laboratory has established protocols for rapidly isolating large numbers of basophils at high purity from human blood, and for growing culture-derived mast cells from human progenitor cells. A variety of assays and techniques are also in place for concurrently detecting cytokines and mediators following a wide range of stimuli. These have facilitated the in vitro testing of numerous anti-allergic drugs for inhibitory activity on basophil and mast cell activation.
Through continued NIH-funding, we are presently involved in studies investigating the role that innate immunity plays in modulating allergic reactions. These studies also focus on the use of basophils and mast cells, and have additionally incorporated investigations probing the biology of specific dendritic cells that express IgE receptors. Particular emphasis relates to the Toll-Like Receptors (TLR) found on these cells and how microbial-derived ligands interacting with these receptors induce phenotypic changes and modify function in these cells. Our progress in this area has revealed evidence for high levels of TLR9 protein in basophils, with its ligand, CpG-DNA, possessing inhibitory activity on the IL-4 and IL-13 produced by basophils. These in vitro studies are also linked to our ongoing collaborations with clinical colleagues, where we are actively investigating mechanisms underlying the efficacy of a novel CpG oligodeoxynucleotide-based therapeutic vaccine that is undergoing clinical trials for ragweed immunotherapy.
John T. Schroeder
Assistant Professor of Medicine – senior laboratory investigator
Senior laboratory Technician
Last Updated: 7/31/10