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Updated: Aug 20, 2026
Murine Cervical Heart Transplantation Model Using a Modified Cuff Technique
Published on: October 12, 2014
CCR4-deficient mice show prolonged graft survival in a chronic cardiac transplant rejection model
Norbert Hüser1, Christine Tertilt, Klaus Gerauer
1Department of Surgery, Technische Universität München, Munich, Germany.
Abstract:
Chronic graft rejection mediated by cellular immune responses still poses a serious clinical problem in transplant surgery. Chemokines coordinate the recruitment of leukocytes in inflammatory and immune responses. Their precise functions in the rejection of allografts are still ill defined. This study investigates the role of chemokine receptor 4 (CCR4) in acute and chronic cardiac allograft rejection in mice. Allogeneic hearts were transplanted into CCR4 deficient (CCR4(-/-)) and control recipients. Reverse transcription-PCR showed transcription of macrophage-derived chemokine and thymus and activation-regulated chemokine, the cognate chemokine ligands of CCR4, within the graft. Compared to wild-type controls, acute allograft rejection in CCR4(-/-) recipients was only slightly prolonged. In contrast, in a gallium nitrate chronic cardiac allograft rejection model, cardiac graft survival was significantly prolonged in CCR4(-/-) recipients. A relative increase in the percentage of graft infiltrating CD8(+) T cells in CCR4(-/-) recipients was observed 30 days after transplantation and was accompanied by a decrease in CD4(+) T cells. Moreover, the percentage of NK1.1(+)CD3(+) graft-infiltrating cells was significantly reduced on day 5 and day 30 post transplantation. These findings indicate that CCR4 is involved in the recruitment of NK1.1(+)CD3(+) cells into cardiac allografts and clearly establish an important and novel role for CCR4 in chronic graft rejection.
Insights
Chemokine receptor 4 (CCR4) plays a key role in chronic graft rejection. Blocking CCR4 significantly prolonged cardiac allograft survival in mice, highlighting its therapeutic potential.
Area of Science:
- Immunology
- Transplant Surgery
- Molecular Biology
Background:
- Chronic graft rejection remains a significant challenge in transplantation.
- Chemokines guide immune cell migration during inflammatory and immune responses.
- The specific role of chemokine receptor 4 (CCR4) in allograft rejection is not fully understood.
Purpose of the Study:
- To investigate the role of CCR4 in acute and chronic cardiac allograft rejection in a mouse model.
- To determine the impact of CCR4 deficiency on immune cell infiltration within transplanted cardiac allografts.
Main Methods:
- Allogeneic heart transplantation into CCR4-deficient (CCR4(-/-)) and wild-type control mice.
- Analysis of chemokine ligand expression (MDC, TARC) in grafts using RT-PCR.
- Assessment of acute and chronic rejection, graft survival, and immune cell populations (CD8+ T cells, CD4+ T cells, NK1.1+CD3+ cells) via flow cytometry.
Main Results:
- CCR4 deficiency only slightly prolonged acute allograft rejection.
- Cardiac allograft survival was significantly extended in CCR4(-/-) recipients in a chronic rejection model.
- Graft-infiltrating CD8+ T cells increased, while CD4+ T cells decreased in CCR4(-/-) recipients at 30 days post-transplant.
- The infiltration of NK1.1+CD3+ cells into cardiac allografts was significantly reduced in CCR4(-/-) recipients on days 5 and 30.
Conclusions:
- CCR4 is implicated in the recruitment of NK1.1+CD3+ cells into cardiac allografts.
- CCR4 plays a critical and novel role in mediating chronic graft rejection.
- Targeting CCR4 may offer a therapeutic strategy to prevent chronic allograft rejection.
