A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection

Richard Horuk; Carol Clayberger; Alan M. Krensky; Zhaohui Wang; Hermann Josef Gröne; Christian Weber; Kim S C Weber; Peter J. Nelson; Karen May; Mary Rosser; Laura Dunning; Meina Liang; Brad Buckman; Ameen Ghannam; Howard P. Ng; Imadul Islam; John G. Bauman; Guo Ping Wei; Sean Monahan; Wei Xu; R. Michael Snider; Michael M. Morrissey; Joseph Hesselgesser; H. Daniel Perez

doi:10.1074/jbc.M007457200

A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection

Richard Horuk^*, Carol Clayberger, Alan M. Krensky, Zhaohui Wang, Hermann Josef Gröne, Christian Weber, Kim S C Weber, Peter J. Nelson, Karen May, Mary Rosser, Laura Dunning, Meina Liang, Brad Buckman, Ameen Ghannam, Howard P. Ng, Imadul Islam, John G. Bauman, Guo Ping Wei, Sean Monahan, Wei XuR. Michael Snider, Michael M. Morrissey, Joseph Hesselgesser, H. Daniel Perez

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

119 Scopus citations

Abstract

Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.

Original language	English (US)
Pages (from-to)	4199-4204
Number of pages	6
Journal	Journal of Biological Chemistry
Volume	276
Issue number	6
DOIs	https://doi.org/10.1074/jbc.M007457200
State	Published - Feb 9 2001

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

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Horuk, R., Clayberger, C., Krensky, A. M., Wang, Z., Gröne, H. J., Weber, C., Weber, K. S. C., Nelson, P. J., May, K., Rosser, M., Dunning, L., Liang, M., Buckman, B., Ghannam, A., Ng, H. P., Islam, I., Bauman, J. G., Wei, G. P., Monahan, S., ... Perez, H. D. (2001). A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection. Journal of Biological Chemistry, 276(6), 4199-4204. https://doi.org/10.1074/jbc.M007457200

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title = "A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection",

abstract = "Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.",

author = "Richard Horuk and Carol Clayberger and Krensky, {Alan M.} and Zhaohui Wang and Gr{\"o}ne, {Hermann Josef} and Christian Weber and Weber, {Kim S C} and Nelson, {Peter J.} and Karen May and Mary Rosser and Laura Dunning and Meina Liang and Brad Buckman and Ameen Ghannam and Ng, {Howard P.} and Imadul Islam and Bauman, {John G.} and Wei, {Guo Ping} and Sean Monahan and Wei Xu and Snider, {R. Michael} and Morrissey, {Michael M.} and Joseph Hesselgesser and Perez, {H. Daniel}",

year = "2001",

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day = "9",

doi = "10.1074/jbc.M007457200",

language = "English (US)",

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Horuk, R, Clayberger, C, Krensky, AM, Wang, Z, Gröne, HJ, Weber, C, Weber, KSC, Nelson, PJ, May, K, Rosser, M, Dunning, L, Liang, M, Buckman, B, Ghannam, A, Ng, HP, Islam, I, Bauman, JG, Wei, GP, Monahan, S, Xu, W, Snider, RM, Morrissey, MM, Hesselgesser, J & Perez, HD 2001, 'A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection', Journal of Biological Chemistry, vol. 276, no. 6, pp. 4199-4204. https://doi.org/10.1074/jbc.M007457200

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AU - Horuk, Richard

AU - Clayberger, Carol

AU - Krensky, Alan M.

AU - Wang, Zhaohui

AU - Gröne, Hermann Josef

AU - Weber, Christian

AU - Weber, Kim S C

AU - Nelson, Peter J.

AU - May, Karen

AU - Rosser, Mary

AU - Dunning, Laura

AU - Liang, Meina

AU - Buckman, Brad

AU - Ghannam, Ameen

AU - Ng, Howard P.

AU - Islam, Imadul

AU - Bauman, John G.

AU - Wei, Guo Ping

AU - Monahan, Sean

AU - Xu, Wei

AU - Snider, R. Michael

AU - Morrissey, Michael M.

AU - Hesselgesser, Joseph

AU - Perez, H. Daniel

PY - 2001/2/9

Y1 - 2001/2/9

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AB - Chemokines like RANTES appear to play a role in organ transplant rejection. Because RANTES is a potent agonist for the chemokine receptor CCR1, we examined whether the CCR1 receptor antagonist BX471 is efficacious in a rat heterotopic heart transplant rejection model. Treatment of animals with BX471 and a subtherapeutic dose of cyclosporin (2.5 mg/kg), which is by itself ineffective in prolonging transplant rejection, is much more efficacious in prolonging transplantation rejection than animals treated with either cyclosporin or BX471 alone. We have examined the mechanism of action of the CCR1 antagonist in in vitro flow assays over microvascular endothelium and have discovered that the antagonist blocks the firm adhesion of monocytes triggered by RANTES on inflamed endothelium. Together, these data demonstrate a significant role for CCR1 in allograft rejection.

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A Non-peptide Functional Antagonist of the CCR1 Chemokine Receptor Is Effective in Rat Heart Transplant Rejection

Abstract

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