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

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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Serial analysis of NK cell and macrophage infiltration of cardiac allogr...
Serial analysis of NK cell and macrophage infiltration of cardiac allografts. Allografts (3/group) were harvested on day 0 (pretransplant) and 1, 3, and 7 days after transplant, and the extent (mean ± SD, 20 fields/graft) of NK cell (DX3+) and macrophage (F4/80+) infiltration was determined. (a) The number of intragraft NK cells peaked at day 3 and was significantly decreased on days 1 and 3 in the CX3CR1–/– recipients. Administration of CsA decreased NK cell infiltration in both CX3CR1+/+ and CX3CR1–/– mice (*P < 0.001, ** P < 0.005). On day 3 after transplant in the presence of CsA there were fewer NK cells in the CX3CR1–/– recipients than in the CX3CR1+/+ mice (P < 0.05). (b) Macrophage recruitment at days 3 and day 7 after transplant was diminished by CsA (*P < 0.001 comparing no CsA versus plus CsA). Macrophage recruitment was most depressed in CX3CR1–/– recipients in the presence of CsA (P < 0.01 comparing CX3CR1+/+ versus CX3CR1–/– recipients at day 3 after transplant; P < 0.001 comparing these same groups at day 7).