title: Anti-OX40L monoclonal antibody prolongs secondary heart allograft survival based on CD40/CD40L and LFA-1/ICAM-1 blockade.
abstract: BACKGROUND
  Memory T cells (Tms) form a barrier against long-term allograft survival; however, CD4(+)Foxp3(+) regulatory T cells (Tregs) can suppress allograft rejection. The OX40/OX40L pathway is critical to the generation of Tms and turns off Treg suppressor function.
  
  
  METHODS
  B6 mice that rejected BALB/c skin grafts after 4 weeks were used as the secondary heart transplant recipients. The skin recipient mice, termed S0, S2 and S3, were treated with the isotype antibodies, anti-CD40L/LFA-1 or anti-OX40L combined with anti-CD40L/LFA-1 mAbs, respectively. The secondary heart recipients, termed H0 and H2, received anti-CD40L/LFA-1 mAbs or not, respectively (Fig. 1).
  
  
  RESULTS
  Four weeks after primary skin transplantation, the Tms in the S3 group that received anti-OX40L with anti-CD40L/LFA-1 mAbs were reduced compared to those in the S2 group (CD4(+) Tm: 32.61 ± 2.20% in S2 vs. 25.36 ± 1.16% in S3; CD8(+) Tm: 27.76 ± 1.96% in S2 vs. 20.95 ± 1.30% in S3; P < 0.01). Meanwhile, the proportions of Tregs in S3 increased compared to those in S2 (P < 0.05). The anti-OX40L with anti-CD40L/LFA-1 mAbs group (S3H2) prolonged the mean survival time (MST) following secondary heart transplantation from 9.5 days to 21 days (P < 0.001). Furthermore, allogeneic proliferation of recipient splenic T cells and graft-infiltrating lymphocytes were significantly inhibited in the S3H2 group. Additionally, a higher level of IL-10 was detected in sera and allografts.
  
  
  CONCLUSIONS
  Anti-OX40L mAb could prolong secondary heart allograft survival based on CD40/CD40L and LFA-1/ICAM-1 blockade. The mechanism of protecting allografts using anti-OX40L mAb involved impairing the generation of Tm and up-regulating IL-10 producing Tregs, inhibiting the function of T cells.
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Helong
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Fenghua
authors.initials: F
authors.lastname: Peng
authors.affiliation: Department of Cardiology, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Lin
authors.affiliation: Organ Transplantation Institute, Xiamen University, Fujian Province, PR China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Gongbin
authors.initials: G
authors.lastname: Lan
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Xubiao
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Fang
authors.affiliation: Malmö Hospital of Lund University, Malmö, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Corbascio
authors.affiliation: Organ Transplantation Institute, Xiamen University, Fujian Province, PR China.
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.affiliation: Department of Urological Organ Transplantation, Center of Organ Transplantation, Second Xiangya Hospital, Central South University, Hunan Province, PR China. Electronic address: penglk2014@163.com.
authors.forename: Longkai
authors.initials: L
authors.lastname: Peng
mesh_terms: D064591:Allografts; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053278:OX40 Ligand; D016038:Skin Transplantation; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000276:immunology*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D019013:CD40 Antigens; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand
keywords: Anti-OX40L mAb; Heart transplantation; Memory T cell; Regulatory T cell