David P. Huston, M.D.
Adjunct Professor, Departments of Medicine and Pathology & Immunology
Professor, Institute of Biosciences and Technology, Texas A&M Health Science Center
M.D., Wake Forest University, Bowman Gray School of Medicine
Postdoctoral, Baylor College of Medicine and National Institutes of Health
Research Interests: Immunobiology of Interleukin-5
The focus of this laboratory is to understand mechanisms regulating inflammation and thereby develop strategies for modulating immune responses. One project focuses on the structure and function of interleukin-5 (IL-5), which is an important cytokine in the pathogenesis of allergies and asthma. We have engineered the gene for IL-5 from several species into eukaryotic expression systems and generated a panel of species-specific anti-IL-5 monoclonal antibodies (mAb) to map function epitopes on interspecies IL-5 chimeras. Insertional mutagenesis and site-directed mutagenesis are being used to delineate residues directly involved in receptor engagement, thereby enabling development of therapeutic IL-5 antagonists. Toward this goal, we have used molecular modeling and genetic engineering to create a biologically active IL-5 monomer which has facilitated the design and engineering of novel small molecule IL-5 antagonists. IL-5-specific signal transduction pathways are also being elucidated as potential therapeutic targets. In addition, a mouse model of asthma has been established in which to study the therapeutic potential of IL-5 antagonists. A second project focuses on the structure and function of the heterodimeric IL-5 receptor (IL-5R). Phosphorylated/ dephosphorylated intracellular proteins affected by IL-5R ligation are being identified by immunoprecipitations, Western blot, and microarray to construct a model detailing the cascade of intracellular events for cell activation. In addition, we have elucidated a novel pathway of proteosome-mediated termination of signal transduction and initiation of receptor endocytosis that leads to heterotypic desensitization of cells to bc receptor engaging cytokines, IL-5, IL-3, and GM-CSF. A novel pathway of IL-5-induced the beta-C repression of alternative splicing of the transmembrane and soluble isoforms of the IL-5R alpha chain is also being delineated. These studies should provide insight into physiologic mechanisms regulating allergic inflammation and enable development of novel therapeutics. Funding for these studies include grants from the National Institutes of Health, foundations, industry, and endowments.
Dickason RR, MM Huston, DP Huston (1996). Delineation of IL-5 domains predicted to engage the IL-5 receptor complex. J Immunol 156:1030-1037.
Dickason RR, DP Huston (1996). Creation of a biologically active interleukin-5 monomer. Nature 379:652-655.
Bressler RB, J Lesko, ML Jones, M Wasserman, RR Dickason, MM Huston, SW Cook, DP Huston (1997). Production of IL-5 and granulocyte-macrophage colony-stimulating factor by naive human mast cells activated by high-affinity IgE receptor ligation. J Allergy Clin Immunol 99(4):508-514.
Hamilos DL, A Kamif, DYM Leung, DP Huston, R Wood, Q Hamid: GM-CSF, IL-5 and RANTES mRNA expression and immunoreactivity in chronic hyperplastic sinusitis with nasal polyposis (NP). Clin Exp Allergy 28(9):1145-1152, 1998.
Shardonofsky FR, J Venzor, R Barrios, K-P Leong, DP Huston: Therapeutic efficacy of an anti-IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma. J Allergy Clin Immunol 104(1):215-221, 1999.
Martinez-Moczygemba M, DP Huston: Proteosome regulation of bc signalling: A novel mechanism for cytokine receptor heterotypic desensitization. J Clin Invest 108:1797-1806, 2001.
Huang J, M Martinez-Moczygemba, A Nguyen, DP Huston: Modulating the interleukin-5 response in asthma. In: Lung Biology in Health and Disease: Therapeutic Targets of Airway Inflammation. NT Eissa and DP Huston, eds. Marcel-Dekker, Inc. New York, 177:495-518, 2003.
Martinez-Moczygemba M, DP Huston: Biology of Beta-c signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol. 112(11):653-665, 2003.
Lei JT,DP Huston, M Martinez-Moczygemba. Molecular signals regulating ubiquitination and proteasome degradation of the common beta chain for the IL-5, IL-3, and GM-CSF receptors. J. Immunol. submitted.
Nguyen, A, G Tavana, M Martinez-Moczygemba, DP Huston: Inhibition of IL-5 signaling by novel synthetic peptides. (In preparation.)
For a complete list of Dr. Huston's publications, visit PubMed.