Contact Details:
Richard L. Stevens, Ph.D.
Brigham and Women's Hospital
Dept. Med.; Div. Rheumatol., Immunol., Allergy
Smith Bldg., Rm. 616B
1 Jimmy Fund Way
Boston, MA 02115
Tel: 617-525-1231
Fax: 617-525-1310
E-mail: rstevens@rics.bwh.harvard.edu

Research Interests:
My research is focused on the molecular and cell biology of mast cells (MCs) and other effector cells that participate in varied inflammatory processes. In regard to the MC, these immune cells release a diverse array of biologically active molecules (including cytokines, chemokines, leukotrienes, prostaglandins, amines, proteoglycans, and proteases) when activated through their high-affinity IgE receptors. The presence of increased numbers of activated MCs in the skin of mastocytoma patients, in the bronchial airways of individuals with asthma and chronic allergies, in the skin of patients undergoing extensive fibrosis, in the intestines of helminth infected individuals, in tumors of cancer patients, and in the joints of patients afflicted with rheumatoid arthritis suggest that these effector cells play central roles in a number of inflammatory disorders. Numerous studies have suggested that MCs also play important roles in development. For example, transgenic mice that lack the mouse MC chymase mMCP-5 possess developmental defects in their eyes with variable penetrance. MCs also play important roles in innate immunity, particularly during bacteria infections. In this regard, mMCP-6 and its human ortholog tryptase βI regulate the extravasation of neutrophils into bacteria-infected tissues.

Mammalian MCs are a heterogeneous family of hematopoietic cells whose ultimate phenotype is dependent on the tissue microenvironment the mature cell eventually resides. In vitro and molecular biology approaches have been developed to identify the factors that regulate the differentiation and phenotypic properties of MCs. In this regard, a new cation-dependent, MC-restricted guanine exchange factor/phorbol ester receptor (designated as RasGRP4) has been identified that appears to be essential for the development of mature MCs. This signaling protein controls what proteases and eicosanoids MCs eventually express. By varying the culture conditions, we and others have been able to induce bone marrow progenitor cells to differentiate and mature into populations of MCs that have varied phenotypes. We have identified a number of novel human and mouse MC-specific genes; we are now investigating why and how these genes and their transcripts are regulated as the MC's microenvironment is altered. Cis-acting elements and trans-acting DNA-binding proteins that regulate transcription of these genes and RNA-binding proteins that regulate the stability of their transcripts are being identified. Transgenic mice have been created that differ substantially in the number of MCs that they have in their tissues. A transgenic/adoptive transfer approach also has been developed in order to address the role of varied MC-derived factors. Recombinant MC-derived proteases have been generated in order to evaluate their physiologic function. What happens to T cells, epithelial cells, endothelial cells, neurons, fibroblasts, chondrocytes, and smooth muscle cells when they interact with MCs and their granule proteases also are being investigated. The consequences of HIV-1 infection of human MCs and their progenitors is another area of investigation.

http://www.hms.harvard.edu/dms/immunology/fac/Stevens.html