Mark H. Kaplan, PhD

The overall focus of my laboratory over more than 20 years has been on understanding the transcriptional regulation of T helper cells as they regulate inflammatory immunity. This line of research began when as a postdoctoral fellow we generated STAT4- and STAT6-deficient mice. The early years of my laboratory’s work continued the characterization of STAT4 and STAT6 function, working at multiple levels, from examining gene regulatory mechanisms and chromatin modifications, to defining how factors control cellular function and inflammatory disease in mouse model system, to finally trying to take observations to using human and patient samples to demonstrate the link between basic research and human immune-mediated health and disease.

My laboratory’s multi-level approach, performing hard-core studies on transcription factor-dependent gene regulation, defining transcription factor-mediated changes in cell function in vitro and in vivo, and ultimately showing conservation in human samples and where possible, linkage to human disease, continues to be a strength in our studies.

STAT proteins in regulation of inflammation
Over the past two decades we have made considerable progress in understanding how STAT proteins regulate the development of T helper subsets. More recently, we have focused on defining the function of STAT4 in non-T cells and we are exploring roles of STAT4 in anti-bacterial immunity and autoimmunity.

Almost two decades ago we developed a mouse model transgenic for a constitutively active STAT6 in T cells. These mice are predisposed towards spontaneous allergic inflammation, particularly in the skin. We have characterized the pathogenesis of skin inflammation and ongoing work is examining changes in the skin responses following injury.  

IL-9 immunobiology
Among the most recent subsets of T cells described, Th cells that are primed for production of IL-9 still have functions that are underappreciated. As we have focused on these cells in the last decade we have defined regulatory elements in the Il9 gene, defined transcription factors that contribute to regulation of IL-9 and defined functions of mast cells including control of mast cell homeostasis in mucosal tissues during allergic inflammation. Current projects are exploring control of mast cells in more mechanistic depth.

In chronic airway inflammation we have defined a resident memory population of T cells that secrete IL-9. In a memory model, these IL-9 secreting T cells are critical for the development of recall responses to allergen. Within this model, we have defined IL-9 responding cells including structural cells in the airways, macrophages, B cells, and innate lymphoid cells. Ongoing work is exploring the generation and maintenance of these cells and further exploring the IL-9 targets that contribute to allergic memory responses. 

In defining the function of IL-9 beyond mast cells we have identified macrophages as important targets for IL-9-stimulated biology in multiple contexts. IL-9 responsiveness in macrophages is critical for the development of allergic inflammation. Moreover, macrophages are required for the pro-tumorigenic activity of IL-9 in the growth of lung tumors. Ongoing work will define IL-9-dependent macrophage functions that contribute to these immune environments.

Allergic disease
We have developed numerous collaborations to explore other aspects of allergic disease. We collaborate with the Dent lab on regulation of the IgE response in vivo, examining the relative roles of Th2, Tfh, and Tfr cells in generating high affinity IgE antibodies. We are collaborating with the Cook-Mills lab in examining neonatal models of atopic dermatitis. Finally, we are collaborating with Basar Bilgicer, a biochemical engineer at University of Notre Dame who has developed novel reagents that inhibit allergen-stimulated IgE responses. We have established efficacy in a humanized mouse model and are working towards testing the inhibitor in patient populations.