TY - JOUR
T1 - Memory T cells mediate cardiac allograft vasculopathy and are inactivated by Anti-OX40L monoclonal antibody
AU - Wang, Hao
AU - Zhang, Zhixiang
AU - Tian, Weijun
AU - Liu, Tong
AU - Han, Hongqiu
AU - Garcia, Bertha
AU - Li, Xian C.
AU - Du, Caigan
N1 - Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
KW - Anti-OX40L antibody therapy
KW - Cardiac allograft vasculopathy
KW - Heart transplantation
KW - Memory T cell
KW - OX40 pathway
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U2 - 10.1007/s10557-013-6502-9
DO - 10.1007/s10557-013-6502-9
M3 - Article
C2 - 24254032
AN - SCOPUS:84897061290
SN - 0920-3206
VL - 28
SP - 115
EP - 122
JO - Cardiovascular Drugs and Therapy
JF - Cardiovascular Drugs and Therapy
IS - 2
ER -