Cardiovascular Drugs and Therapy

, Volume 28, Issue 2, pp 115–122 | Cite as

Memory T Cells Mediate Cardiac Allograft Vasculopathy and are Inactivated by Anti-OX40L Monoclonal Antibody

ORIGINAL ARTICLE

Abstract

Purpose

Cardiac allograft vasculopathy (CAV) is a major complication limiting the long-term survival of cardiac transplants. The role of memory T cells (Tmem) in the pathogenesis of CAV remains elusive. This study investigated the role of Tmem cells in the development of CAV and the therapeutic potential of targeting the OX40/OX40L pathway for heart transplant survival.

Methods

Tmem cells were generated in Rag-1-/- C57BL/6 (B6) mice by homeostatic proliferation (HP) of CD40L null CD3+ T cells from B6 mice. Rag-1-/- B6 mice (H-2b) harboring Tmem cells received cardiac allografts from BALB/c mice (H-2d), and were either untreated or treated with anti-OX40L monoclonal antibody (mAb) (0.5 mg/mouse/day) for 10 days.

Results

Six weeks after HP, the majority of transferred CD40L-/- T cells in Rag-1-/- B6 mice were differentiated to CD44high and CD62Llow Tmem cells. BALB/c heart allografts in Rag-1-/- B6 recipient mice in the presence of these Tmem cells developed a typical pathological feature of CAV; intimal thickening, 100 days after transplantation. However, functionally blocking the OX40/OX40L pathway with anti-OX40L mAb significantly prevented CAV development and reduced the Tmem cell population in recipient mice. Anti-OX40L mAb therapy also significantly decreased cellular infiltration and cytokine (IFN-γ, TNF-α and TGF-β) expression in heart allografts.

Conclusions

Tmem cells mediate CAV in heart transplants. Functionally blocking the OX40/OX40L pathway using anti-OX40L mAb therapy prevents Tmem cell-mediated CAV, suggesting therapeutic potential for disrupting OX40-OX40L signaling in order to prevent CAV in heart transplant patients.

Keywords

Heart transplantation Cardiac allograft vasculopathy Memory T cell OX40 pathway Anti-OX40L antibody therapy 

Notes

Acknowledgments

The authors are grateful to Wei Ge for technical assistance, and Mr. Jeffrey Helm for editorial assistance.

Conflict of Interest

None of the authors have any conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hao Wang
    • 1
  • Zhixiang Zhang
    • 1
  • Weijun Tian
    • 1
  • Tong Liu
    • 1
  • Hongqiu Han
    • 1
  • Bertha Garcia
    • 2
  • Xian C. Li
    • 3
  • Caigan Du
    • 4
  1. 1.Department of General SurgeryTianjin Medical University General Hospital, Tianjin General Surgery InstituteTianjinChina
  2. 2.Department of PathologyThe University of Western OntarioLondonCanada
  3. 3.Department of MedicineHarvard Medical SchoolBostonUSA
  4. 4.Department of Urologic SciencesThe University of British ColumbiaVancouverCanada

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