Donald MacGlashan Jr., MD, PhD

Professional Titles

• Senior Laboratory Investigator

Primary Academic Title

Professor of Medicine

Background

Centers and Institutes

Asthma and Allergy Center

Research Interests

Mechanisms of signal transduction

Lab Website

David MacGlashan Laboratory

• Research in the Donald MacGlashan Laboratory aims to understand the regulation of secretion from human basophils and mast cells--two cells thought to play key roles in allergic reactions and other diseases. The hallmark reaction in these cells is degranulation through cell-bound IgE. Our interests lie in the signaling mechanisms that control this dramatic cell response and the factors that regulate the degree of the reaction.

Research Summary

For the last 40 years, this laboratory has focused on understanding the regulation of secretion from human basophils and mast cells.  These two cell types are considered central participants in the allergic reaction as well as having a variety of other physiological or pathophysiological roles in other diseases. For these two cell types, there is a hallmark reaction, degranulation in response to stimulation through cell bound Ige antibody. The morphological changes in the cell structure are often extreme as the cell re-organizes itself to extrude granules and generate other mediators associated with the allergic response.  Our interests lie in how the cells make the transition, i.e., the signaling mechanisms that control this dramatic cell response and the factors that regulate the extent of the reaction. This laboratory has been involved in a wide variety of projects. Some examples, going back to the early 1980s, include: First, methods of purification of both human basophils and tissue mast cells that resulted in sufficient cells to engage in mechanistic studies of secretion.  A fruitful association with mathematical biologists involved in characterizing the nature and functional significance of the cell surface aggregating reaction leading to mediator secretion. A long-standing project to characterize the secretion of non-granule mediators from both mast cells and basophils. For example, we first demonstrated the IgE-mediated generation of leukotrienes from both human mast cells and basophils. Studies in the mid-1990s also established some of the characteristics of cytokine secretion from these two cell types. Studies throughout the late 1980s and 1990s have addressed whether these cells undergo secretion in an all-or-nothing manner. More generally, we have had a basic interest in the characteristics of the single cell response and how it differs from what is observed in the average population response. Much of this work centered on the characteristics of cytosolic calcium signaling. There has also been a long history in developing a better understanding of how cytokines modify basophil or mast cell function. Much of the effort has focused on how interleukin-3 upregulates human basophil function.

Over the four decades of research, we have sought to understand the signal transduction pathways involved in secretion but, in particular (and in distinction with elegant studies others have done in cell lines), the relationship of known signaling pathways to the differences in cell function observed in the general human population. This project has identified a critical element in the signal transduction reaction that is started by the crosslinking of cell surface FceRI (high affinity IgE receptor). In humans, the critical element is the expression level of SYK, a penultimate tyrosine kinase associated with FceRI after crosslinking initiates the reaction.  Many of the functional characteristics of the peripheral blood basophil and their role in disease expression can be linked to expression levels of SYK in basophils. The fact that the regulated expression of SYK in basophils and mast cells is unique to these cells has led to the recent projects to understand the unique control mechanisms of SYK expression.

Projects related to signal transduction have branched in many directions. Activation signal transduction is only one side of the coin, de-activation signal transduction is the other. Projects in this laboratory also examine how the cell turns off an ongoing reaction with an eye towards how this information can be used to therapeutic advantage. One longstanding project relates to the role of critical tyrosine kinases in down-regulation and the recognition that it is possible to inhibit these kinases to stop secretion from these cells without stopping the termination reactions also begun by crosslinking FceRI.  Coupling this information with the development of selective tyrosine kinase inhibitors offers some distinct therapeutic opportunities. For example, the identification of BTK as another critical tyrosine kinase in the IgE-mediated reaction, that its inhibition does not halt desensitization, and that we have recently shown the remarkable efficacy of BTK inhibitors in preventing peanut reactions (a project led by Dr. Melanie Dispenza), suggests an opportunity to use this therapeutic to shut down basophil and mast cell secretion by a mechanism that is unique.

Another longstanding project has been to understand regulation of cell surface FceRI expression on basophils and mast cells.  After demonstrating that IgE itself regulates the expression of the receptor to which it binds, FceRI, this project series has been examining how this regulation determines the expression of allergic disease. This work has led my laboratory in several directions.

One was to join in the development of, at the time (1987), a new therapeutic approach to treating allergic diseases. In collaboration with Tanox, Inc., and later with Genentech after its acquisition of Tanox, anti-IgE antibody was developed. It was the first biologic therapeutic in the allergy “space”. This development became the product now known as Xolair which was approved for the treatment of allergic asthma by the FDA in 2003. It has subsequently been approved for the treatment of chronic spontaneous urticaria in 2014 and food allergy in 2024. From this laboratory’s perspective, the use of this therapeutic provided many new opportunities to explore the role of IgE antibody and the regulation of FceRI in the expression of human allergic diseases and new insights have resulted from human subject’s research using this therapeutic tool.

One example is the discovery that SYK expression appears to determine the efficacy of Xolair. This has been observed for all three conditions for which Xolair is approved. Current studies are examining how this observation comes about. And, the observation has led to the identification of a genetic determinant of SYK expression. This observation is the basis for the hypothesis that knowledge of the SYK polymorphisms may be provide a predictor of therapeutic efficacy for this drug.

Visit my website, www.basophil.net, you will find a button link ‘Other basophil studies and Chat GPT-based bot that can answer all questions specifically related to my research. It is actually quite good despite some occasional LLM issues that happen with Chatbots.

Selected Publications

• MacGlashan, D. W., Jr. and B. J. Undem (2008). "Inducing an Anergic State in Mast Cells and Basophils without Secretion." J. Allergy Clin. Immunol. 121(6): 1500-1506.
• MacGlashan, D. W., Jr. and S. S. Saini (2017). "Syk expression and IgE-mediated histamine release in basophils as biomarkers for predicting the clinical efficacy of omalizumab." J Allergy Clin Immunol 139(5): 1680-1682 e1610.
• Peng, X., M. Zhao, L. Gao, R. Sen and J. MacGlashan, D.W. (2020). "Identifying Regulatory Pathways of SYK Expression in Human Basophils." J Allergy Clin Immunol 145: 947-957.
• MacGlashan, D., Jr. and L. Gao (2023). "Association of a SYK promoter polymorphism with SYK expression and IgE-mediated histamine release." Clin Exp Allergy 53(5): 573-576.
• Suresh, R. V., C. Dunnam, D. Vaidya, R. A. Wood, B. S. Bochner, D. W. MacGlashan, Jr. and M. C. Dispenza (2023). "A phase II study of Bruton's tyrosine kinase inhibition for the prevention of anaphylaxis." J Clin Invest 133(16).

Additional Training

Johns Hopkins University School of Medicine, Baltimore, MD, 1983, Research postdoctoral fellowship, Allergy & Clinical Immunology