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      Met-RANTES Inhibition of Mucosal Perfusion Failure in Acute Intestinal Transplant Rejection – Role of Endothelial Cell-Leukocyte Interaction


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          Acute rejection-induced microvascular injury results in graft dysfunction, ultimately leading to graft loss. Infiltration of T cells and monocytes as a consequence of an enhanced endothelial cell-leukocyte interaction appears to play an important role in this deleterious process. Recruitment of these pro-inflammatory cells to the vessel wall is mediated by chemokines such as RANTES. Heterotopic small bowel transplantation was performed in rats with the fully allogeneic Brown Norway-Lewis strain combination and, as a control, the syngeneic Lewis-Lewis strain combination. Intravital microscopy was performed from postoperative day 1–7 in both groups. The percentages of perfused villi and villus stasis, mucosal and muscular functional capillary densities, red blood cell velocities, and finally, firm adherence of leukocytes in postcapillary submucosal venules were assessed. Syngeneic small bowel transplantation revealed homogeneous perfusion of villi and muscle layers over the whole study period. Allogeneic small bowel transplantation showed a decline in perfusion from postoperative day 1 until complete failure on postoperative day 7. This was accompanied by a continuous increase in endothelial cell-leukocyte interaction which reached a plateau on postoperative day 5. Met-RANTES treatment at 200 µg/day for 5 days markedly attenuated both the decrease in functional capillary density and the increased endothelial cell-leukocyte interaction in rats following allogeneic small bowel transplantation. We conclude that blocking chemokine receptors, thereby limiting endothelial cell-leukocyte interaction, may constitute a useful therapeutic approach to the prevention of microcirculatory perfusion failure in acute transplant rejection.

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          RANTES and MCP-3 antagonists bind multiple chemokine receptors.

          Antagonists of multiple chemokines could be more effective than inhibitors of specific chemokines for controlling cell migration and inflammation. To attempt to identify such antagonists we characterized a number of truncated analogs of regulated on activation normal T cell expressed protein (RANTES), monocyte chemoattractant protein (MCP)-3, and MCP-1. On the basis of their ability to compete for binding of their parent chemokines, three analogs were selected for cross-reactivity studies: RANTES (9-68), MCP-3 (10-76), and MCP-1 (9-76). These analogs bound to THP-1 monocytic cells with dissociation constants that were within 4-6-fold of their native counterparts, but they did not promote detectable chemotaxis of THP-1 cells or enzyme release from purified human monocytes. The RANTES (9-68) analog competed for the binding and inhibited the activities of all three chemokines. In contrast, native RANTES was specific for RANTES binding sites. However, truncation of either MCP-1 or MCP-3 did not change their respective binding specificity. MCP-3 and MCP-3 (10-76) competed for binding of all three labeled chemokines. MCP-1 (9-76) competed strongly for binding of labeled MCP-1, but only weakly for the other two labeled ligands and inhibited the activities induced by MCP-1 and MCP-3 but not RANTES. Although RANTES (9-68) and MCP-3 (10-76) inhibited all three chemokines, the RANTES analog was significantly more potent for RANTES-induced activity. The results indicate that NH2-terminal residues partly determine the receptor specificity of RANTES, and deletions within this region permit binding to multiple chemokine receptors. The findings suggest the feasibility of design of high affinity multi-specific CC chemokine antagonists.

            Author and article information

            J Vasc Res
            Journal of Vascular Research
            S. Karger AG
            February 2002
            13 February 2002
            : 39
            : 1
            : 51-58
            Departments of aSurgery and bCardiovascular Physiology, University of Göttingen, Göttingen and cDepartment of Cellular and Molecular Pathology, University of Heidelberg/German Cancer Research Centre, Heidelberg, Germany; dSerono Pharmaceutical Research Institute, Geneva, Switzerland
            48993 J Vasc Res 2002;39:51–58
            © 2002 S. Karger AG, Basel

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            Page count
            Figures: 5, Tables: 1, References: 22, Pages: 8
            Research Paper


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