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.

Recent Selected Publications

Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM: Ultrastructural localization of platelet endothelial cell adhesion molecule (PECAM-1, CD31) in vascular endothelium. J Histochem Cytochem 52: 87-101, 2004.

Dvorak AM, Sciuto TE. Mouse spleen basophils. Int Arch Allergy Immunol 134: 332-333, 2004.

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 - 517, 2004.

Sun JF, Phung T, Shiojima I, Felske T, Upalakalin JN, Feng D, Kornaga T, Dor T, Dvorak AM, Walsh K, Benjamin LE. Microvascular patterning is controlled by fine-tuning the Akt signal. Proc Natl Acad Sci 102: 128-133, 2005.

Satchi-Fainaro R, Mamluk R, Wang L, Short SM, Nagy JA, Feng D, Dvorak AM, Dvorak HF, Puder M, Mukhopadhyay D, Folkman J. Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer Cell 7: 251-261, 2005.

Flaumenhaft R, Dilks JR, Rozenvayn N, Monahan-Earley RA, Feng D, Dvorak AM. The actin cytoskeleton differentially regulates alpha-granule and dense granule secretion. Blood 105: 3879-87, 2 005.

Dvorak, AM. In: Dvorak AM (vol 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.

Dvorak AM, Feng D. Vesiculo-vacuolar organelles are permeability structures in the endothelium of normal and tumor microvessels. In: Shepro D, ed. Microvascular Research: Biology and Pathology. Elsevier, San Diego, 293-297, 2005.

Chatterjea D, Burns SM, Sciuto TE, Dvorak AM, Contag CH, Galli SJ. Adoptive transfer of mast cells does not enhance the impaired survival of Kit W/Kit W-v mice in a model of low dose intraperitoneal infection with bioluminescent Salmonella typhimurium. Immunol Lett 99: 122-9, 2005.

Yang L, Froio RM, Sciuto TE, Dvorak AM, Alon R, Luscinskas FW. ICAM-1 regulates neutrophil adhesion and transcellular migration of TNF-a activated vascular endothelium under flow. Blood 5 2005, in press.