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Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection
Christopher A. Haskell, … , James B. Rottman, Israel F. Charo
Christopher A. Haskell, … , James B. Rottman, Israel F. Charo
Published September 1, 2001
Citation Information: J Clin Invest. 2001;108(5):679-688. https://doi.org/10.1172/JCI12976.
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Article

Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection

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Abstract

Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX3CR1, the receptor for Fk. CX3CR1–/– mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX3CR1–/– and CX3CR1+/+ mice had similar levels of proteinuria and injury. CX3CR1–/– and CX3CR1+/+ mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX3CR1–/– and CX3CR1+/+ recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX3CR1–/– mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX3CR1–/– recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX3CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.

Authors

Christopher A. Haskell, Wayne W. Hancock, David J. Salant, Wei Gao, Vilmos Csizmadia, Wendy Peters, Kerrie Faia, Omar Fituri, James B. Rottman, Israel F. Charo

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Figure 4

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Cell types adhering to Fk. (a) Peripheral blood leukocytes from CX3CR1+/...
Cell types adhering to Fk. (a) Peripheral blood leukocytes from CX3CR1+/+ mice were isolated as a buffy coat and either spun onto a glass slide (cytospin) or allowed to adhere to Ab- tethered Fk (Fk-adherent). Cells were then labeled with biotinylated Ab’s (CD3 or CD11b) and fluorescent streptavidin for identification. Bright-field and fluorescent images were captured. (b) Quantitation of cell types binding to Fk. Three fields were counted for each labeling condition, and the percentage of each cell type in the input population and Fk-adherent population is shown. The experiment shown is representative of two. (c) Adhesion of purified NK and T cells to Fk. NK (NK1.1+, CD3–) and T (CD3+, NK1.1–) cells were purified and fluorescently labeled. Cells were allowed to adhere to Ab-tethered Fk, in the presence or absence of soluble (100 nM) Fk. The experiment shown is representative of three. The asterisk indicates P < 0.005.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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