Memory T cells mediate cardiac allograft vasculopathy and are inactivated by Anti-OX40L monoclonal antibody

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 CD62L low 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: T mem 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. © 2013 Springer Science+Business Media New York.