Cardiovascular Drugs and Therapy

, Volume 28, Issue 2, pp 115–122 | Cite as

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

  • Hao Wang
  • Zhixiang Zhang
  • Weijun Tian
  • Tong Liu
  • Hongqiu Han
  • Bertha Garcia
  • Xian C. Li
  • Caigan Du



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.


Heart 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.


  1. 1.
    Murphy L, Pinney SP. Clinical outcomes following heart transplantation. Mt Sinai J Med. 2012;79(3):317–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Taylor DO, Edwards LB, Boucek MM, Trulock EP, Aurora P, Christie J, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult heart transplant report–2007. J Heart Lung Transplant. 2007;26(8):769–81.PubMedCrossRefGoogle Scholar
  3. 3.
    Gaudin PB, Rayburn BK, Hutchins GM, Kasper EK, Baughman KL, Goodman SN, et al. Peritransplant injury to the myocardium associated with the development of accelerated arteriosclerosis in heart transplant recipients. Am J Surg Pathol. 1994;18(4):338–46.PubMedCrossRefGoogle Scholar
  4. 4.
    Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res. 2006;99(8):801–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg. 2005;48(4):319–27.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Eisen H, Ross H. Optimizing the immunosuppressive regimen in heart transplantation. J Heart Lung Transplant. 2004;23(5 Suppl):S207–13.PubMedCrossRefGoogle Scholar
  7. 7.
    Kurtulus S, Tripathi P, Hildeman DA. Protecting and rescuing the effectors: roles of differentiation and survival in the control of memory T cell development. Front Immunol. 2012;3:404.PubMedCentralPubMedGoogle Scholar
  8. 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
  9. 9.
    Hagemeijer MC, van Oosterhout MF, van Wichen DF, van Kuik J, Siera-de Koning E, Gmelig Meyling FH, et al. T cells in cardiac allograft vasculopathy are skewed to memory Th-1 cells in the presence of a distinct Th-2 population. Am J Transplant. 2008;8(5):1040–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Brook MO, Wood KJ, Jones ND. The impact of memory T cells on rejection and the induction of tolerance. Transplantation. 2006;82(1):1–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Calderhead DM, Buhlmann JE, van den Eertwegh AJ, Claassen E, Noelle RJ, Fell HP. Cloning of mouse OX40: a T cell activation marker that may mediate T-B cell interactions. J Immunol. 1993;151(10):5261–71.PubMedGoogle Scholar
  12. 12.
    Godfrey WR, Fagnoni FF, Harara MA, Buck D, Engleman EG. Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J Exp Med. 1994;180(2):757–62.PubMedCrossRefGoogle Scholar
  13. 13.
    So T, Lee SW, Croft M. Immune regulation and control of regulatory T cells by OX40 and 4-1BB. Cytokine Growth Factor Rev. 2008;19(3–4):253–62.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Zaini J, Andarini S, Tahara M, Saijo Y, Ishii N, Kawakami K, et al. OX40 ligand expressed by DCs costimulates NKT and CD4+ Th cell antitumor immunity in mice. J Clin Invest. 2007;117(11):3330–8.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Zingoni A, Sornasse T, Cocks BG, Tanaka Y, Santoni A, Lanier LL. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions. J Immunol. 2004;173(6):3716–24.PubMedGoogle Scholar
  16. 16.
    Baumann R, Yousefi S, Simon D, Russmann S, Mueller C, Simon HU. Functional expression of CD134 by neutrophils. Eur J Immunol. 2004;34(8):2268–75.PubMedCrossRefGoogle Scholar
  17. 17.
    Stuber E, Strober W. The T cell B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response. J Exp Med. 1996;183(3):979–89.PubMedCrossRefGoogle Scholar
  18. 18.
    Croft M. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol. 2010;28:57–78.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000;165(6):3043–50.PubMedGoogle Scholar
  20. 20.
    Croft M, So T, Duan W, Soroosh P. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229(1):173–91.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Ishii N, Takahashi T, Soroosh P, Sugamura K. OX40-OX40 ligand interaction in T-cell-mediated immunity and immunopathology. Adv Immunol. 2010;105:63–98.PubMedCrossRefGoogle Scholar
  22. 22.
    Salek-Ardakani S, Croft M. Regulation of CD4 T cell memory by OX40 (CD134). Vaccine. 2006;24(7):872–83.PubMedCrossRefGoogle Scholar
  23. 23.
    Soroosh P, Ine S, Sugamura K, Ishii N. Differential requirements for OX40 signals on generation of effector and central memory CD4+ T cells. J Immunol. 2007;179(8):5014–23.PubMedGoogle Scholar
  24. 24.
    Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–77.PubMedCrossRefGoogle Scholar
  25. 25.
    Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005;5(3):465–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Valujskikh A, Lakkis FG. In remembrance of things past: memory T cells and transplant rejection. Immunol Rev. 2003;196:65–74.PubMedCrossRefGoogle Scholar
  27. 27.
    Tan JT, Ernst B, Kieper WC, LeRoy E, Sprent J, Surh CD. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med. 2002;195(12):1523–32.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Goldrath AW, Bogatzki LY, Bevan MJ. Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation. J Exp Med. 2000;192(4):557–64.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Murali-Krishna K, Ahmed R. Cutting edge: naive T cells masquerading as memory cells. J Immunol. 2000;165(4):1733–7.PubMedGoogle Scholar
  30. 30.
    Shimizu K, Schonbeck U, Mach F, Libby P, Mitchell RN. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. J Immunol. 2000;165(6):3506–18.PubMedGoogle Scholar
  31. 31.
    Wu Z, Wang Y, Gao F, Shen X, Zhai Y, Kupiec-Weglinski JW. Critical role of CD4 help in CD154 blockade-resistant memory CD8 T cell activation and allograft rejection in sensitized recipients. J Immunol. 2008;181(2):1096–102.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Zhai Y, Meng L, Gao F, Busuttil RW, Kupiec-Weglinski JW. Allograft rejection by primed/memory CD8+ T cells is CD154 blockade resistant: therapeutic implications for sensitized transplant recipients. J Immunol. 2002;169(8):4667–73.PubMedGoogle Scholar
  33. 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
  34. 34.
    Wang H, Arp J, Liu W, Faas SJ, Jiang J, Gies DR, et al. Inhibition of terminal complement components in presensitized transplant recipients prevents antibody-mediated rejection leading to long-term graft survival and accommodation. J Immunol. 2007;179(7):4451–63.PubMedGoogle Scholar
  35. 35.
    Wang H, Hosiawa KA, Min W, Yang J, Zhang X, Garcia B, et al. Cytokines regulate the pattern of rejection and susceptibility to cyclosporine therapy in different mouse recipient strains after cardiac allografting. J Immunol. 2003;171(7):3823–36.PubMedGoogle Scholar
  36. 36.
    Racusen LC, Halloran PF, Solez K. Banff 2003 meeting report: new diagnostic insights and standards. Am J Transplant. 2004;4(10):1562–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Vu MD, Clarkson MR, Yagita H, Turka LA, Sayegh MH, Li XC. Critical, but conditional, role of OX40 in memory T cell-mediated rejection. J Immunol. 2006;176(3):1394–401.PubMedGoogle Scholar
  38. 38.
    Gerberick GF, Cruse LW, Miller CM, Sikorski EE, Ridder GM. Selective modulation of T cell memory markers CD62L and CD44 on murine draining lymph node cells following allergen and irritant treatment. Toxicol Appl Pharmacol. 1997;146(1):1–10.PubMedCrossRefGoogle Scholar
  39. 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
  40. 40.
    Schuler T, Hammerling GJ, Arnold B. Cutting edge: IL-7-dependent homeostatic proliferation of CD8+ T cells in neonatal mice allows the generation of long-lived natural memory T cells. J Immunol. 2004;172(1):15–9.PubMedGoogle Scholar
  41. 41.
    Zhang P, Manes TD, Pober JS, Tellides G. Human vascular smooth muscle cells lack essential costimulatory molecules to activate allogeneic memory T cells. Arterioscler Thromb Vasc Biol. 2010;30(9):1795–801.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Ge W, Jiang J, Liu W, Lian D, Saito A, Garcia B, et al. Regulatory T cells are critical to tolerance induction in presensitized mouse transplant recipients through targeting memory T cells. Am J Transplant. 2010;10(8):1760–73.PubMedCrossRefGoogle Scholar
  43. 43.
    Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, et al. Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med. 1997;186(9):1407–18.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Lalvani A, Brookes R, Hambleton S, Britton WJ, Hill AV, McMichael AJ. Rapid effector function in CD8+ memory T cells. J Exp Med. 1997;186(6):859–65.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Zimmermann C, Prevost-Blondel A, Blaser C, Pircher H. Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences. Eur J Immunol. 1999;29(1):284–90.PubMedCrossRefGoogle Scholar
  46. 46.
    Hoflich C, Docke WD, Busch A, Kern F, Volk HD. CD45RAbright/CD11abright CD8+ T cells: effector T cells. Int Immunol. 1998;10(12):1837–45.PubMedCrossRefGoogle Scholar
  47. 47.
    Huibers M, De Jonge N, Van Kuik J, Koning ES, Van Wichen D, Dullens H, et al. Intimal fibrosis in human cardiac allograft vasculopathy. Transpl Immunol. 2011;25(2–3):124–32.PubMedCrossRefGoogle Scholar
  48. 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
  49. 49.
    Tellides G, Pober JS. Interferon-gamma axis in graft arteriosclerosis. Circ Res. 2007;100(5):622–32.PubMedCrossRefGoogle Scholar
  50. 50.
    Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH, Schechner JS, et al. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature. 2000;403(6766):207–11.PubMedCrossRefGoogle Scholar
  51. 51.
    Kirkiles-Smith NC, Tereb DA, Kim RW, McNiff JM, Schechner JS, Lorber MI, et al. Human TNF can induce nonspecific inflammatory and human immune-mediated microvascular injury of pig skin xenografts in immunodeficient mouse hosts. J Immunol. 2000;164(12):6601–9.PubMedGoogle Scholar
  52. 52.
    Shi M, Ye Z, Umeshappa KS, Moyana T, Xiang J. Alpha tumor necrosis factor contributes to CD8+ T cell survival in the transition phase. Biochem Biophys Res Commun. 2007;360(3):702–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Davis R, Pillai S, Lawrence N, Sebti S, Chellappan SP. TNF-alpha-mediated proliferation of vascular smooth muscle cells involves Raf-1-mediated inactivation of Rb and transcription of E2F1-regulated genes. Cell Cycle. 2012;11(1):109–18.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Carter LL, Zhang X, Dubey C, Rogers P, Tsui L, Swain SL. Regulation of T cell subsets from naive to memory. J Immunother. 1998;21(3):181–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Hao Wang
    • 1
  • Zhixiang Zhang
    • 1
  • Weijun Tian
    • 1
  • Tong Liu
    • 1
  • Hongqiu Han
    • 1
  • Bertha Garcia
    • 2
  • Xian C. Li
    • 3
  • Caigan Du
    • 4
  1. 1.Department of General SurgeryTianjin Medical University General Hospital, Tianjin General Surgery InstituteTianjinChina
  2. 2.Department of PathologyThe University of Western OntarioLondonCanada
  3. 3.Department of MedicineHarvard Medical SchoolBostonUSA
  4. 4.Department of Urologic SciencesThe University of British ColumbiaVancouverCanada

Personalised recommendations