- Dr. Risto Renkonen, Principal Investigator
- Dr. John B. Lowe, Co-Investigator
- The Haartman Institute, University of Helsinki, Helsinki, Finland
- Prevention of Tranplant Rejections by Blocking White Cell Traffic into Grafts
Acute heart allograft rejection is characterized by heavy infiltration of white cells, namely lymphocytes. To infiltrate the graft and thus promote rejection, the lymphocytes extravasate from blood through the vascular endothelial layer into the graft parenchyma. Extravasation of lymphocytes is initiated by an interaction of members of the selectin family and their oligosaccharide-containing ligands. L-selectin is expressed on leukocyte surfaces and recognizes its endothelial protein counterreceptors, provided that they are decorated with properly a 1,3-fucosylated glycans, the prototype decoration being sialyl Lewis x (sLex) for L-selectin. Importantly, endothelium under normal conditions does not express proper glycoforms of L-selectin ligands. However, proinflammatory stimuli in our in vitro, animal and most recently human heart transplantation patients studies have shown that endothelium can be induced to express these glycans de novo and to promote leukocyte extravasation. A novel approach to increase immunosuppressive efficacy, without targeting to activation and proliferation of T cells, would be to inhibit the carbohydrate-dependent entry of lymphocytes into the graft.
Our work with experimental animals has demonstrated that free sLex-containing glycans can prevent short-term selectin-dependent inflammation, for example, after reperfusion injury. With rat heart and kidney allograft models, we have shown a strong induction of sLex-decorated L-selectin ligands on only microvascular endothelium occurring concomitantly with the accumulation of lymphocytes into the grafts. The proposal focuses on the use of novel selectin-ligand knockout mice in heart transplantation experiments. Here we address the role of selectin ligands to the initiation of allograft rejection.