The underlying theme of this proposal is that molecular homing mechanisms are responsible for the accumulation of lymphocytes in salivary tissue in primary Sjogren s syndrome. The investigators hypothesize that recruitment and retention of these cells is due to activation or expression of specific adhesion molecules on glandular endothelial cells. They further hypothesize that prevention of attachment of lymphocytes to glandular endothelium through blockage of adhesion molecules may prevent disease progression.
The specific aims are: 1) to identify pertinent lymphocyte and salivary endothelium adhesion molecules in two animal models of Sjogren s syndrome, and 2) to block the lymphocyte-endothelium interaction with specific antibodies, """"""""disintegrins,"""""""" and synthetic peptides using in vitro techniques. Two strains of mice which develop Sjogren s-like changes (lymphocytic infiltrates) in their salivary glands will serve as donors of tissues and cells. Three procedures will be used to address the hypothesis. First, standard immunohistochemical staining methods will be used to identify adhesion molecules on lymphocytes and endothelium in frozen tissue sections from salivary glands (and other organs). Second, an established lymphocyte adhesion assay will be done on frozen sections of salivary glands to determine 1) the relative importance of the adhesion molecules identified, and 2) the relative potency of antibodies, """"""""disintegrins,"""""""" and peptides to block lymphocyte-endothelium adhesion. Third, tissue culture techniques will be used in an attempt to selectively grow salivary gland endothelial cells in vitro. Adhesion molecule expression will be assessed in cultured cells following activation with various cytokines.
| Brando, C; Marcinkiewicz, C; Goldman, B et al. (2000) EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine alpha4 integrin and attenuates lymphocyte infiltration of Langerhans islets in pancreas and salivary glands in nonobese diabetic mice. Biochem Biophys Res Commun 267:413-7 |
| Marcinkiewicz, C; Calvete, J J; Marcinkiewicz, M M et al. (1999) EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits alpha4 and alpha5 integrins in an RGD-independent manner. J Biol Chem 274:12468-73 |
| Danen, E H; Marcinkiewicz, C; Cornelissen, I M et al. (1998) The disintegrin eristostatin interferes with integrin alpha 4 beta 1 function and with experimental metastasis of human melanoma cells. Exp Cell Res 238:188-96 |
| McLane, M A; Marcinkiewicz, C; Vijay-Kumar, S et al. (1998) Viper venom disintegrins and related molecules. Proc Soc Exp Biol Med 219:109-19 |
