Lymphocyte homing to sites of inflammation is directed by the interaction between adhesion molecules on the vascular endothelium and their ligands on the surface of the lymphocytes. The homing of lymphocytes bearing the proper ligands to specific organs may be determined by the selective expression of vascular adhesion molecules. It is my hypothesis that the microvascular endothelium of the skin has a characteristic profile expression of the adhesion molecules E-Selectin, VCAM-1, and ICAM-1 that differs from other tissues as a function of cytokine responsiveness and duration of adhesion molecule expression. I will determine whether these tissue specific differences in endothelial adhesion molecule expression result in the selective recruitment of subsets of lymphocytes bearing specific adhesion molecule ligands. This will be accomplished by 1) constructing a chimeric human-immunodeficient mouse model in which to compare the interactions between human lymphocytes and endothelial cells derived from skin, lung, subcutaneous fat and umbilical vein; 2) systematically characterizing tissue specific differences in adhesion molecule expression in response to cytokine stimulation in vitro (in both organ and cell culture) and in vivo; 3) determining whether specific combinations of adhesion molecules are necessary for the recruitment of specific T cell subsets in vivo by first inoculating the chimeric animals with whole or alloreactive cell depleted human PBMC, then using blocking antibodies to selectively interfere with adhesion molecule-ligand interactions; 4) determining whether these interactions are sufficient, in the absence of other differences, for selective lymphocyte recruitment by using retroviral transduction to alter the repertoire of endothelial adhesion molecule expression, and assessing the effect on the phenotype of infiltrating T-cells. A five year mentored program is proposed test this hypothesis. This program will incorporate training in the fields of immunology and molecular biology under the guidance of a mentor (J. Pober) with a well established background in immunobiology and vascular biology, collaborators (A. Bothwell and M. Kluger) with expertise in molecular biology, as well as from numerous courses and seminars. At the end of this period it is my goal to be well established as an independent investigator, and to have made a contribution to the understanding of cutaneous lymphocyte recruitment which could be exploited in the development of anti inflammatory agents with specific activity in the skin.
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|Schechner, Jeffrey S; Crane, Saara K; Wang, Feiya et al. (2003) Engraftment of a vascularized human skin equivalent. FASEB J 17:2250-6|