Ann M. Dvorak, MD
Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN 235
Boston, MA 02215
Dvorak Lab >>
Ann Dvorak earned an M.D. from the University of Vermont Medical School in 1963. After becoming Board Certified in Pediatrics and Pathology she did a postdoctoral fellowship with Morris Karnovsky at Harvard Medical School. Multiple faculty and staff positions in Boston followed. She became Professor of Pathology at HMS in 1991. She joined the Department of Pathology at Beth Israel Deaconess Medical Center in 1979 where she remains. She directs electron microscopy in the CVBR.
Basophil, Mast Cell, Eosinophil and Endothelial Cell Biology
Mast cells and basophils represent critical effector cells in IgE-dependent hypersensitivity responses. While mast cells and basophils importantly contribute to the pathogenesis of acute allergic reactions, these cell types also participate in many other biological responses in which their role is less clear. We are evaluating whether certain of the important biological functions of basophils and mast cells are expressed via " piecemeal degranulation " of these cells, in which histamine and other mediators are transported between the cytoplasmic granules and the plasma membrane within small, membrane-bound cytoplasmic vesicles. In contrast to anaphylactic degranulation, which results in the rapid release of large quantities of basophil or mast cell mediators, we have proposed that piecemeal degranulation may permit the slow and/or sustained release of histamine and other basophil or mast cell-derived mediators. Accordingly, piecemeal degranulation of basophils and mast cells may contribute to the persistence of the inflammation that is associated with certain IgE-independent reactions.
We are also evaluating whether the augmented vascular permeability, which has been identified in several types of inflammation, including settings that are characterized by piecemeal degranulation of mast cells or basophils, reflects enhanced formation and/or function of endothelial cell vesiculo-vacuolar organelles (VVOs), rather than transport through classical interendothelial cell gaps such as those that develop in postcapillary venules immediately after the administration of large amounts of histamine. We have shown that VVOs represent the major transendothelial cell route by which circulating macromolecules extravasate from tumor vessels. However, their importance in the augmented vascular permeability that is observed in other settings including those which are associated with piecemeal degranulation of basophils or mast cells, remains to be determined.
To test these hypotheses, we are performing in vitro and in vivo experiments to quantify the extent of basophil or mast cell histamine released by piecemeal degranulation. Also, we are performing in vivo experiments to assess the extent to which VVOs contribute to the augmented vascular permeability that is observed in settings associated with piecemeal as opposed to anaphylactic degranulation of basophils or mast cells.
New and Noteworthy Publications
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Dvorak AM. Electron microscopic-facilitated understanding of endothelial cell biology. Contributions established in the 1950s and 1960s. In: Endothelial Biomedicine. Aird WC, ed. Cambridge University Press, Cambridge, pp.643-656, 2007.
A review of electron microscopic contributions in endothelial cell biology concentrates on the 1950's and 1960's and emphasizes how these approaches facilitated our newer analysis of vascular function (s) in the 1990's.
Carman CV, Sage PT, Sciuto TE, de la Fuete MA, Geha RS, Ochs HD, Dvorak HF,
Dvorak AM, Springer TA. (2007) Trans-cellular diapedesis is initiated by leukocyte podosomes. Immunity 26, p784.
This study, initiated by C.V. Carman, shows the power of a combined confocal microscopic and electron microscopic approach to the study of inflammation. Also, the effectiveness of the integration of these two labs in the CVBR is illustrated.
Spencer LA, Melo RC, Perez SA, Bafford SP,
Dvorak AM, Weller PF. Cytokine receptor-mediated trafficking of preformed Il-4 in eosinophils identifies an innate immune mechanism of cytokine secretion. Proc Natl Acad Sci U S A 103:3333-3338, 2006.
Eosinophil cell biology is presented here where an ultrastructural immunogold analysis revealed a receptor-mediated pathway and organelles involved therein in Il-4 intracellular trafficking.
Dvorak, AM. In: Dvorak AM (volume ed), Ultrastructure of Mast Cells and Basophils, Vol 85. Series eds. Ring J, Adorini L, Berek C, Blaser K, Capron M, Denburg J, Holgate S, Marone G, Saito H. Chemical Immunology and Allergy. S. Karger, Basel, 2005: 1-351.
This book contains 10 chapters, which cover the key contributions to the understanding of mast cell and basophil cell biology made in our laboratory in the 1990's.
Min B, Prout M, Hu-Li J, Zhu J, Jankovic D, Morgan ES, Urban JR Jr.,
Dvorak AM, Finkelman FD, LeGros G, Paul WE. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med 200: 507 to 517, 2004.
Our role in this key study indicating basophil production of Il-4 in a parasite model was to verify the identification of the mouse basophil.