CCR4 expression on host T cells is a driver for alloreactive responses and lung rejection
Vyacheslav Palchevskiy, … , David G. Brooks, John A. Belperio
Vyacheslav Palchevskiy, … , David G. Brooks, John A. Belperio
Published May 14, 2019
Citation Information: JCI Insight. 2019;4(12):e121782. https://doi.org/10.1172/jci.insight.121782.
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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 1

Draining allograft recipient lymph nodes have increased expression of CCL17 and CCL22.

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Draining allograft recipient lymph nodes have increased expression of CC...
BALB/c airways were transplanted subcutaneously into C57BL/6 recipients (allografts), as compared with C57BL/6 airways transplanted into C57BL/6 recipients (isografts). Whole allograft draining nodes were harvested on days 7, 14, and 21 for protein analysis. (A) Protein concentrations of CCL17 and CCL22 by Luminex from whole draining node homogenates from allograft and isograft recipients. (B and C) Representative IHC staining for CCL17 and CCL22, as compared with appropriate control Abs from allograft draining lymph nodes or sham-operated CCR4+/+ mouse lymph nodes on day 7. Allograft recipient CCL17 protein is expressed morphologically from HEVs, as compared with virtually no staining in CCR4+/+ sham-operated controls or for the control Ab. In allograft recipients, CCL22 protein is detected morphologically on mononuclear phagocytes in the paracortical and subcapsular sinus, as compared with just a few mononuclear phagocytes only in the subcapsular sinus from the CCR4+/+ sham-operated controls and virtually no staining for the control Ab. Protein data are representative of 4–9 mice per group. Error bars indicate SEM. Significance was determined by Mann-Whitney U test; *P < 0.05. IHC experiments involve n = 4 nodes from 4 different allograft recipients.