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 7

CTLA4-Ig combined with CCR4–/– recipients leads to long-term allograft accommodation in 2 models of allograft rejection.

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CTLA4-Ig combined with CCR4–/– recipients leads to long-term allograft a...
CTLA4-Ig given i.p. at 0.2 mg on day 0 prior to airway transplantation, and rejection was evaluated on days 2, 4, and 6 after transplant to CCR4–/– as compared with CCR4+/+. (A) Rejection scores for CTLA4-Ig–treated CCR4–/– and CCR4+/+ allograft recipients on days 42 and 126. See also Supplemental Figure 6. (B) Day 126 representative H&E staining of airway allografts from CCR4–/– and CCR4+/+ recipients given CTLA4-Ig. CTLA4-Ig given to CCR4–/– recipients results in virtually normal airways with intact ciliated epithelium and no fibro-obliteration. CTLA4-Ig given to CCR4+/+ recipients leads to airways that are rejected, without epithelium, and invaded by fibroblasts causing fibro-obliteration. A section of airway allograft is magnified to show the presence of the epithelial layer in CTLA4-Ig + CCR4–/– and absence of the epithelial layer with fibro-obliteration in CTLA4-Ig + CCR4+/+ recipients. CCR4–/– and CCR4+/+ orthotopic single-lung transplant recipients were given CTLA4-Ig i.p. (0.1 mg) on day 0 just prior to transplant (Tx). Original magnification, ×5 (left panels), ×20 (right panels). (C) Day 126 representative elastin trichrome staining shows that CTLA4-Ig given to CCR4+/+ allograft recipients leads to high-grade vascular, airway, and pleural rejection with fibrosis. (D) Day 126 representative elastin trichrome staining shows that CTLA4-Ig given to CCR4–/– allograft recipients leads to virtually normal lung allografts. Data are representative of 4–12 mice per group. Original magnification, ×5 (top panels), ×20 (bottom panels). Error bars indicate SEM. Significance was determined by Mann-Whitney U test; *P < 0.05.