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Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection
Wei Gao, … , Craig J. Gerard, Wayne W. Hancock
Wei Gao, … , Craig J. Gerard, Wayne W. Hancock
Published January 1, 2000
Citation Information: J Clin Invest. 2000;105(1):35-44. https://doi.org/10.1172/JCI8126.
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Article

Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection

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Abstract

Although mononuclear cell infiltration is a hallmark of cellular rejection of a vascularized allograft, efforts to inhibit rejection by blocking leukocyte-endothelial cell adhesion have proved largely unsuccessful, perhaps in part because of persistent generation of chemokines within rejecting grafts. We now provide, to our knowledge, the first evidence that in vivo blockade of specific chemokine receptors is of therapeutic significance in organ transplantation. Inbred mice with a targeted deletion of the chemokine receptor CCR1 showed significant prolongation of allograft survival in 4 models. First, cardiac allografts across a class II mismatch were rejected by CCR1+/+ recipients but were accepted permanently by CCR1–/– recipients. Second, CCR1–/– mice rejected completely class I– and class II–mismatched BALB/c cardiac allografts more slowly than control mice. Third, levels of cyclosporin A that had marginal effects in CCR1+/+ mice resulted in permanent allograft acceptance in CCR1–/– recipients. These latter allografts showed no sign of chronic rejection 50–200 days after transplantation, and transfer of CD4+ splenic T cells from these mice to naive allograft recipients significantly prolonged allograft survival, whereas cells from CCR1+/+ mice conferred no such benefit. Finally, both CCR1+/+ and CCR1–/– allograft recipients, when treated with a mAb to CD4, showed permanent engraftment, but these allografts showed florid chronic rejection in the former strain and were normal in CCR1–/– mice. We conclude that therapies to block CCR1/ligand interactions may prove useful in preventing acute and chronic rejection clinically.

Authors

Wei Gao, Peter S. Topham, Jennifer A. King, Stephen T. Smiley, Vilmos Csizmadia, Bao Lu, Craig J. Gerard, Wayne W. Hancock

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Figure 1

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Detection of CCR1 expression after mouse cardiac allografting. (a) In si...
Detection of CCR1 expression after mouse cardiac allografting. (a) In situ hybridization studies of a day 5 allograft in a CCR1+/+ mouse, using a digoxygenin-labeled antisense probe, shows CCR1 mRNA expression by diffusely distributed leukocytes; (b) specificity of labeling was shown by lack of blue/violet staining using a corresponding sense probe. (c) Higher magnification of immunoperoxidase-stained cardiac allografts shows dense CCR1 expression by infiltrating mononuclear cells (brown reaction product) in a CCR1+/+ mouse, whereas (d) no CCR1 protein was detected in allografts within CCR1–/– recipients. (Cryostat sections, in situ hybridization, a and b, have no counterstain. ×100. Immunoperoxidase, c and d, have a hematoxylin counterstain. ×400. Data are representative of 4 grafts per group.)

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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