Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines

R. Langer, Mouer Wang, Stanislaw M. Stepkowski, Wayne W. Hancock, Rongxiang Han, Ping Li, Lily Feng, Robert A. Kirken, Kurt L. Berens, Brian Dupre, Hemangshu Podder, Richard A F Dixon, Barry D. Kahan

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 H 2O [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 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-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-α, and IFN-γ 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.

Original languageEnglish
Pages (from-to)2893-2901
Number of pages9
JournalJournal of the American Society of Nephrology
Volume15
Issue number11
DOIs
Publication statusPublished - Nov 2004

Fingerprint

Selectins
Chemokines
Allografts
Cytokines
Kidney
Interleukin-1
L-Selectin
Infusion Pumps
Interleukin-18
E-Selectin
Sirolimus
Interleukin-12
Ribonucleases
Interleukin-4
Interleukin-10
Immunosuppression
Cyclosporine
Interleukin-2
Blood Vessels
bimosiamose

ASJC Scopus subject areas

  • Nephrology

Cite this

Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines. / Langer, R.; Wang, Mouer; Stepkowski, Stanislaw M.; Hancock, Wayne W.; Han, Rongxiang; Li, Ping; Feng, Lily; Kirken, Robert A.; Berens, Kurt L.; Dupre, Brian; Podder, Hemangshu; Dixon, Richard A F; Kahan, Barry D.

In: Journal of the American Society of Nephrology, Vol. 15, No. 11, 11.2004, p. 2893-2901.

Research output: Contribution to journalArticle

Langer, R, Wang, M, Stepkowski, SM, Hancock, WW, Han, R, Li, P, Feng, L, Kirken, RA, Berens, KL, Dupre, B, Podder, H, Dixon, RAF & Kahan, BD 2004, 'Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines', Journal of the American Society of Nephrology, vol. 15, no. 11, pp. 2893-2901. https://doi.org/10.1097/01.ASN.0000142425.23036.AC
Langer, R. ; Wang, Mouer ; Stepkowski, Stanislaw M. ; Hancock, Wayne W. ; Han, Rongxiang ; Li, Ping ; Feng, Lily ; Kirken, Robert A. ; Berens, Kurt L. ; Dupre, Brian ; Podder, Hemangshu ; Dixon, Richard A F ; Kahan, Barry D. / Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines. In: Journal of the American Society of Nephrology. 2004 ; Vol. 15, No. 11. pp. 2893-2901.
@article{4cb2ec4f313b4253b4c14fe7d7dcdde4,
title = "Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines",
abstract = "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 H 2O [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 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-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-α, and IFN-γ 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.",
author = "R. Langer and Mouer Wang and Stepkowski, {Stanislaw M.} and Hancock, {Wayne W.} and Rongxiang Han and Ping Li and Lily Feng and Kirken, {Robert A.} and Berens, {Kurt L.} and Brian Dupre and Hemangshu Podder and Dixon, {Richard A F} and Kahan, {Barry D.}",
year = "2004",
month = "11",
doi = "10.1097/01.ASN.0000142425.23036.AC",
language = "English",
volume = "15",
pages = "2893--2901",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "11",

}

TY - JOUR

T1 - Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines

AU - Langer, R.

AU - Wang, Mouer

AU - Stepkowski, Stanislaw M.

AU - Hancock, Wayne W.

AU - Han, Rongxiang

AU - Li, Ping

AU - Feng, Lily

AU - Kirken, Robert A.

AU - Berens, Kurt L.

AU - Dupre, Brian

AU - Podder, Hemangshu

AU - Dixon, Richard A F

AU - Kahan, Barry D.

PY - 2004/11

Y1 - 2004/11

N2 - 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 H 2O [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 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-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-α, and IFN-γ 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.

AB - 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 H 2O [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 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-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-α, and IFN-γ 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.

UR - http://www.scopus.com/inward/record.url?scp=16644369039&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16644369039&partnerID=8YFLogxK

U2 - 10.1097/01.ASN.0000142425.23036.AC

DO - 10.1097/01.ASN.0000142425.23036.AC

M3 - Article

C2 - 15504942

AN - SCOPUS:16644369039

VL - 15

SP - 2893

EP - 2901

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 11

ER -