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

作者：Wang, Hao^*; Zhang, Zhixiang; Tian, Weijun; Liu, Tong; Han, Hongqiu; Garcia, Bertha; Li, Xian C.; Du, Caigan

来源：Cardiovascular Drugs and Therapy, 2014, 28(2): 115-122.

DOI：10.1007/s10557-013-6502-9

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

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.
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.
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-gamma, TNF-alpha and TGF-beta) expression in heart allografts.
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.

• 出版日期2014-4
• 单位天津医科大学