CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection
Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio
Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio
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Research Article Immunology Transplantation

CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection

Abstract

Despite current immunosuppressive strategies, long-term lung transplant outcomes remain poor due to rapid allogenic responses. Using a stringent mouse model of allo-airway transplantation, we identified the CCR4-ligand axis as a central node driving secondary lymphoid tissue homing and activation of the allogeneic T cells that prevent long-term allograft survival. CCR4 deficiency on transplant recipient T cells diminished allograft injury and when combined with CTLA4-Ig led to lung allograft accommodation lasting longer than in any previous study to our knowledge. Thus, we identify CCR4-ligand interactions as a central mechanism driving allogeneic transplant rejection and suggest it as a potential target to enhance long-term lung transplant survival.

Authors

Vyacheslav Palchevskiy, Ying Ying Xue, Rita Kern, Stephen S. Weigt, Aric L. Gregson, Sophie X. Song, Michael C. Fishbein, Cory M. Hogaboam, David M. Sayah, Joseph P. Lynch III, Michael P. Keane, David G. Brooks, John A. Belperio

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Figure 2

CCR4–/– recipients of airway allografts attenuate rejection.

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CCR4–/– recipients of airway allografts attenuate rejection. BALB/c airw...
BALB/c airways subcutaneously transplanted into CCR4–/– and CCR4+/+ recipients and their allografts were analyzed for rejection scores. (A) Rejection scores for donor BALB/c airways as well as allografts from either the CCR4–/– or CCR4+/+ recipients on days 7, 14, 21, and 28. (B) Representative H&E staining of allografts from CCR4–/– and CCR4+/+ recipients on day 21. CCR4–/– recipients have limited intraluminal inflammation (red arrows), virtually normal epithelium (green arrows), and minimal matrix deposition without fibroblasts obstructing the lumen (i.e., fibro-obliteration). A section of the allograft is magnified to highlight the presence of a normal epithelial layer in the airway allografts from the CCR4–/– recipients. Allografts from the CCR4+/+ recipients have a moderate amount of intraluminal inflammatory cells (red arrows), absence of airway epithelial cells (purple arrows), and presence of fibroblasts (pink arrows) causing fibro-obliteration of the lumen. See also Supplemental Figure 1. (C) Rejection scores of allografts from recipients treated with either the CCR4 antagonist or appropriate control on day 14. (D) Representative H&E staining of allografts from the CCR4 antagonist and control on day 14. Recipients with the CCR4 antagonist have a virtually normal epithelium and minimal matrix deposition without fibro-obliteration. A section of the allograft is magnified to show the presence of a normal epithelial layer in the airway allografts from the recipients treated with the CCR4 antagonist. Allografts from the control-treated recipients have an absence of airway epithelial cells. Original magnification, ×5. Error bars indicate SEM. Significance was determined by Mann-Whitney U or unpaired t test where appropriate; *P < 0.05.