Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines.
Binding of the P-, L-, and E-selectins to sialyl Lewis(x) (sLe(x)) retards circulating leukocytes, thereby facilitating their attachment to the blood vessels of allografts. Whether the selectin inhibitor bimosiamose (BIMO; C(46)H(54)O(16) . 0.25 H(2)O [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-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-alpha, and IFN-gamma 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.
Langer
Robert
R
Division of Immunology and Organ Transplantation, Department of Surgery, The University of Texas Medical School-Houston, 6431 Fannin, Suite 6.240, Houston, TX 77030, USA.
Wang
Mouer
M
Stepkowski
Stanislaw M
SM
Hancock
Wayne W
WW
Han
Rongxiang
R
Li
Ping
P
Feng
Lily
L
Kirken
Robert A
RA
Berens
Kurt L
KL
Dupre
Brian
B
Podder
Hemangshu
H
Dixon
Richard A F
RA
Kahan
Barry D
BD
D000818:Animals; D018925:Chemokines / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D006586:Hexanes / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008358:Mannose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000473:pathology; D019087:Selectins / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology
D018925:Chemokines; D016207:Cytokines; D006586:Hexanes; D007166:Immunosuppressive Agents; D019087:Selectins; D016572:Cyclosporine; C496819:bimosiamose; D008358:Mannose; D020123:Sirolimus