title: Memory T Cells Mediate Cardiac Allograft Vasculopathy and are Inactivated by Anti-OX40L Monoclonal Antibody.
abstract: OBJECTIVE
  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-2(b)) harboring Tmem 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) 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
  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.
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin General Surgery Institute, Tianjin, China, hwangca272@gmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Weijun
authors.initials: W
authors.lastname: Tian
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Hongqiu
authors.initials: H
authors.lastname: Han
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Xian C
authors.initials: XC
authors.lastname: Li
authors.forename: Caigan
authors.initials: C
authors.lastname: Du
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D016027:Heart Transplantation / Q000009:adverse effects*; D018960:Hyaluronan Receptors / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D019041:L-Selectin / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D053262:Receptors, OX40 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D019041:L-Selectin; D007371:Interferon-gamma