My lab group brings a variety of backgrounds and expertise to the study of the immune system and the genetic, biochemical and cellular processes that serve to regulate normal and aberrant immune activities. Our main research theme is the study of the role that a stress response protein (metallothionein, MT) plays in the immune response. Our hypothesis is that MT made during cellular stress can serve as a “danger signal” to the immune response, and can alter how that response will proceed. We have shown that MT can have dramatic influences on the progression of both innate and adaptive immunity. Changes that can be attributed to MT include effects on the response to infection, and on the severity of autoimmune disease. These influences probably occur as a result of several different contributions that MT can make to mammalian physiology, but one of the more surprising findings from our lab group is the observation that extracellular MT can initiate chemotactic cell movement. This suggests that when there is an extracellular pool of MT, it may influence the trafficking patterns of leukocytes toward sites of cellular stress, and may exacerbate the stress in a positive feedback loop.
A logical consequence of this observation is that in cases where MT is synthesized as a consequence of stresses not associated with a beneficial immune response, the trafficking patterns of leukocytes may be altered in detrimental ways. We have shown that genetic manipulations of MT and anti-metallothionein antibody reagents can alter the immune capacity of the organism, and can alter the severity of inflammatory and autoimmune disease. In collaboration with scientists from the University of Gent we have shown that the anti-metallothionein antibody made in our laboratory can dramatically decrease the severity of inflammatory bowel disease (IBD) in several mouse models of that disease. We have extended these studies to show that our anti-metallothionein antibody can also diminish the severity of type 1 and type 2 diabetes in collaboration with colleagues at the Joslin Diabetes Center/Harvard Medical School, and are currently exploring other applications of the antibody therapeutic with colleagues at the Wadsworth Center of the NY Department of Health. Doctoral students, research associates and undergraduates in the laboratory group are working to more completely define the molecular mechanisms that relate to MT and anti-metallothionein therapeutics. Recently, we have developed a relationship with Biohaven Pharmaceuticals to apply these findings to human disease therapeutics.
As an interesting offshoot of this work, we are also exploring the role of a bacterial protein of the metallothionein family (PmtA), as a virulence factor in bacterial pathogenesis. Our hypothesis is that when bacteria (e.g. Pseudomonas aeruginosa) make and release PmtA, that form of MT may alter the host chemotactic response in ways that prevent an effective host response to the infection.
We are also involved in the development of novel research tools. In collaboration with the Knecht laboratory at UCONN, we developed an automated chemotactic assay that measures cell movement in real time. Using this assay, we can more readily assess the chemotactic potential of new agents (such as MT homologs), and the therapeutic potential of new drugs in a more objective manner. This technology (the ECIS/taxis system) is now commercially available from Applied Biophysics, Inc.
Finally, we have been engaged in a collaboration with Ciencia, Inc. and the NY Department of Health to develop Grating-Coupled Surface Plasmon Resonance Imaging (GCSPRI) and Surface Plasmon enhanced fluorescence (SPEF)-based instruments for the detection and characterization of molecular and cellular biomarker signatures. These high-content assays enable the simultaneous measurement of thousands of analytes from a single sample, with sub-picogram/ml sensitivities.