Lung transplantation has become a recognized treatment of endstage pulmonary disease. Despite the resolution of most technical problems, organ rejection remains the major limitation to widespread application. Organ rejection appears to be mediated by host lymphocytes migrating into the donor lung. Several clinical observations indicate that: the molecules controlling lymphocyte migration into the lung define a more general mechanism of lymphocyte """"""""recruitment"""""""". An important goal for lung transplantation is to define the molecular basis for lymphocyte recruitment into the transplanted lung. This goal has both biologic and therapeutic implications as lymphocyte migration is the first potential regulatory step in lung transplant rejection. The common pathway into the transplanted lung is the transvascular migration of host lymphocytes into the perivascular and alveolar spaces. To define the molecular basis of this lymphocyte recruitment, an experimental approach should address on the membrane molecules involved in the pulmonary lymphocyte-endothelial cell interaction. The role of these membrane molecules, in the context of systemic recirculation patterns and organ specific """"""""homing, can only be addressed in a large animal model with the potential to study lymphocyte recruitment in vivo. The sheep model is the best characterized system of lymphocyte recruitment, has the most molecular reagents of any large animal model, and has ideal anatomy for the in vivo study of lymphocyte recruitment. Based on the experimental opportunities in the sheep system, the following specific aims are proposed: 1) Develop molecular reagents to be used in the sheep model for the study of lymphocyte recruitment into the lung; 2) Characterize the role of endothelial cell adhesion molecules in the regulation of lymphocyte recruitment into the lung; 3) Study the role of lymphocyte membrane molecules in the regulation of lymphocyte homing and recruitment; 4) Confirm the biologic implications of lymphocyte-endothelial cell interactions under physiologic conditions in vitro and in vivo.
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