Memory T Cells Mediate Cardiac Allograft Vasculopathy and are Inactivated by Anti-OX40L Monoclonal Antibody
- 309 Downloads
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.
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.
Six weeks after HP, the majority of transferred CD40L-/- T cells in Rag-1-/- B6 mice were differentiated to CD44high and CD62Llow 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.
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.
KeywordsHeart transplantation Cardiac allograft vasculopathy Memory T cell OX40 pathway Anti-OX40L antibody therapy
The authors are grateful to Wei Ge for technical assistance, and Mr. Jeffrey Helm for editorial assistance.
Conflict of Interest
None of the authors have any conflicts of interest.
- 8.van Loosdregt J, van Oosterhout MF, Bruggink AH, van Wichen DF, van Kuik J, de Koning E, et al. The chemokine and chemokine receptor profile of infiltrating cells in the wall of arteries with cardiac allograft vasculopathy is indicative of a memory T-helper 1 response. Circulation. 2006;114(15):1599–607.PubMedCrossRefGoogle Scholar
- 33.Olfert ED, Cross BM, McWilliam AA. Responsibility for the care and use of experimental animals. In: Olfert ED, Cross BM, McWilliam AA, editors. Guide to the care and use of experimental animals (Vol 1). Ottawa: Association of Universities and Colleges of Canada; 1993. p. 1–14.Google Scholar
- 39.Nakano M, Fukumoto Y, Satoh K, Ito Y, Kagaya Y, Ishii N, et al. Genetic Deletion of Ox40 Ligand Suppresses the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice. J Vasc Res. 2009;46:100.Google Scholar
- 48.Wang Y, Bai Y, Qin L, Zhang P, Yi T, Teesdale SA, et al. Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation. Circ Res. 2007;101(6):560–9.PubMedCrossRefGoogle Scholar