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

Purpose: Cardiac allograft vasculopathy (CAV) is a major complication limiting the long-term survival of cardiac transplants. The role of memory T cells (T_mem) in the pathogenesis of CAV remains elusive. This study investigated the role of T_mem cells in the development of CAV and the therapeutic potential of targeting the OX40/OX40L pathway for heart transplant survival. Methods: T_mem 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-2^b) harboring T_mem cells received cardiac allografts from BALB/c mice (H-2^d), 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 CD44^high and CD62L ^low T_mem cells. BALB/c heart allografts in Rag-1 ^-/- B6 recipient mice in the presence of these T_mem 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 T_mem 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 T_mem cell-mediated CAV, suggesting therapeutic potential for disrupting OX40-OX40L signaling in order to prevent CAV in heart transplant patients.