Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Abstract

Abstract. Binding of the P-, L-, and E-selectins to sialyl Lewis (CI Ͻ1 is synergistic; CI ϭ 1 is additive; and CI Ͼ1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI ϭ 0.64) and FTY720 (CI ϭ 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4 ϩ , CD8 ϩ , and macrophages on day 7 after grafting was observed. Multiple cytokines were also expressed, including IL-1␣, IL-1␤, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-␣, and IFN-␥ in kidney allografts on days 3, 5, and 7 after grafting, as measured by a ribonuclease protection assay. Furthermore, at similar time points, BIMO treatment reduced intragraft expression of P-selectin glycoprotein ligand-1, CX 3 CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.Whereas nearly all cells in an adult human are sessile, the majority of leukocytes provide a mobile defense of the individual's integrity (1). Precursors of leukocytes continuously undergo differentiation in the bone marrow and the thymus, whereas mature leukocytes continuously traffic between the spleen and the lymph nodes. Efficient deployment to an inflammatory site requires polarization, mobilization, and migration of leukocytes during processes that are controlled by adhesion molecules and chemokines (2). These molecules participate in the process of ischemia/reperfusion (I/R), as well as in acute and chronic rejection responses toward organ allografts (3,4).Adhesive interactions with the vascular endothelium initiate the migration of leukocytes to sites of inflammation. In this cascade of events (rolling, attachment, spreading, and transendothelial migration), the selectin family (P-, E-, and L-selectins) is largely involved in rolling and attachment (5). Rolling is initiated by the interaction of selectins with sialyl Lewis x (sLe x ) ligand (6); all selectins have an NH 2 -terminal, lectinlike domain binding to sLe x and other related ligands in a Ca 2ϩ -dependent manner (7). Two selectins are expressed on endothelial cells, namely, P-selectins, which are stored in granules and rapidly translocated to the cell surface, and E-selectins, which are induced by inflammatory cytokines (8). Within minutes after reperfusion, endothelial cells express P-selectins that mediate leukocyte rolling over the vascular lining.The main ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1), which is a disulfide-bonded homodimeric mucin-like glycoprotein expressed on leukocytes, platelets, and CD34 ϩ cells (9). Functional PSGL-1 is modified with sialylation and fucosylation of O-linked sugars, as well as sulfation of tyrosine residues on the N-terminus (10). Engagement of PSGL-1 by P-selectins slows the movement of leukocytes and sparks a cascade of signaling pathways, leading to the expression of multiple adhesion molecules (11). During rolling, the leukocytes start expressing integrins triggered by cytokines and

Update on Mechanisms of Ischemic Acute Kidney Injury

“…Administration of a mAb against the proinflammatory cytokine IL-6 ameliorated structural and functional consequences of ischemic AKI, decreased neutrophil infiltration, and reduced proinflammatory cytokine production (171). Bimosiamose, a novel pan-selectin inhibitor, protected from ischemic AKI in a kidney transplant model by reducing infiltration of macrophages and T cells and inhibiting intragraft expression of chemokines and cytokines (172). In addition to cholesterol lowering in humans, widely used statins possess several properties that may be beneficial in ischemic AKI, including profound anti-inflammatory effects, inhibition of reactive oxygen species, and stimulation of endothelial NO production (173)(174)(175).…”

Blockade of KATP Channels Reduces Endothelial Hyperpolarization and Leukocyte Recruitment upon Reperfusion After Hypoxia

“…In addition, HUVEC are isolated from large veins, while the endothelial inflammatory response associated with ischemia/reperfusion injury is most pronounced in the venular microvasculature (10). (4,(45)(46)(47) or adhesion molecule deficient animals (48,49). Inhibition of selectin function has reduced inflammation and fibrosis in a large animal model of warm and cold ischemia (46 (50,51), however, multicenter randomized trials did not confirm this effect (52); success being limited perhaps by the redundancy of adhesion molecule/leukocyte interactions in vivo (53,54 …”

Importance of Donor- and Recipient-Derived Selectins in Cardiac Allograft Rejection

“…11 Treatment with the potent selectin antagonist bimosiamose was recently reported to inhibit rejection of kidney allografts in a rat model. 12 Because these strategies have indiscriminately targeted both donor and recipient selectins, specific contributions of either donor or recipient selectins in the process of allograft rejection remain to be elucidated. In this study, murine cardiac allografts were performed using mice deficient in all three selectins (ELP Ϫ/Ϫ ) as donor or recipient animals.…”