Memory T Cells Mediate Cardiac Allograft Vasculopathy and are Inactivated by Anti-OX40L Monoclonal Antibody
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- Wang, H., Zhang, Z., Tian, W. et al. Cardiovasc Drugs Ther (2014) 28: 115. doi:10.1007/s10557-013-6502-9
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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.
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.
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.
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.