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*Division of Immunology and Organ Transplantation, Department of Surgery, the University of Texas Medical School, Houston, Texas; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Nephrology, Baylor College of Medicine, Houston, Texas; Department of Integrative Biology and Pharmacology, the University of Texas Medical School, Houston, Texas; and ¶Encysive Pharmaceuticals Inc., Bellaire, Texas
Correspondence to Dr. Stanislaw M. Stepkowski, Division of Immunology and Organ Transplantation, The University of Texas Medical School–Houston, 6431 Fannin, Suite 6.240, Houston, TX 77030. Phone: 713-500-7372; Fax: 713-500-0784; E-mail: Stanislaw.Stepkowski{at}uth.tmc.edu
Binding of the P-, L-, and E-selectins to sialyl Lewisx (sLex) retards circulating leukocytes, thereby facilitating their attachment to the blood vessels of allografts. Whether the selectin inhibitor bimosiamose (BIMO; C46H54O16 · 0.25 H2O [867.4 molecular weight]) inhibits the rejection process of kidney allografts in a rat model was examined. Rat recipients acutely rejected kidney allografts at a mean survival time of 8.8 ± 0.75 d. An intravenous 7-d infusion by osmotic pump of 2.5, 5, 10, or 20 mg/kg BIMO extended kidney allograft survival to 11.5 ± 2.2 d (P < 0.03), 25.4 ± 11.4 d (P < 0.006), 37.4 ± 13.6 d (P < 0.001), and 39.8 ± 34.5 d (P < 0.01), respectively. Combination of BIMO with cyclosporine produced synergistic interactions, as documented by the combination index (CI) values of 0.34 to 0.43 (CI <1 is synergistic; CI = 1 is additive; and CI >1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI = 0.64) and FTY720 (CI = 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4+, CD8+, 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, CX3CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.
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