CD8(+) T cells induce graft vascular occlusion in a CD40 knockout donor/recipient combination

J Heart Lung Transplant. 2003 Feb;22(2):177-83. doi: 10.1016/s1053-2498(02)00465-5.


Background: It has recently been shown that treatment of animals with antibodies to CD154 (CD40L), allows for prolongation of cardiac allograft survival, but does not inhibit development of graft vasculopathy. CD8(+) T cells have been implicated in this effect. In this study we assess the role of CD40-CD154 interactions and CD40-independent CD8(+) T cells in the permanent and complete absence of CD40 by using donors and recipients genetically deficient in CD40.

Methods: Hearts from BALB/c CD40(-/-) donors were transplanted into C57BL/6 CD40(-/-) recipients in the presence or absence of CD8(+) T-cell depletion. At Day 60, hearts were examined for vasculopathy using quantitative morphometry and numbers of infiltrating T cells were counted. The intragraft expression of interferon-gamma (IFN-gamma), transforming growth factor-beta1 (TGF-beta1), interleukin-4 (IL-4), eotaxin and CCR3 was assessed using competitive reverse transcription-polymerase chain reaction (RT-PCR).

Results: In the absence of CD8(+) T-cell depletion, the mean percent intimal occlusion was 28% (with 50% of vessels showing no intimal occlusion). This figure was reduced significantly to 12% and 80% of vessels showing no intimal occlusion in mice receiving anti-CD8 antibody. Depletion of CD8(+) T cells was associated with significantly reduced intragraft IFN-gamma, TGF-beta1 and CCR3 expression, whereas mRNA production of IL-4 and eotaxin was increased.

Conclusion: Vascular intimal occlusion progresses in the complete absence of CD40-CD154 interactions, albeit to quite a small degree. The residual disease is significantly reduced by anti CD8(+) T-cell treatment, confirming the importance of CD40-CD154-independent CD8(+) T cells in the genesis of this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arterial Occlusive Diseases / immunology*
  • CD40 Antigens / immunology*
  • CD40 Ligand / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytokines / immunology
  • Heart Transplantation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tunica Intima / pathology


  • CD40 Antigens
  • Cytokines
  • CD40 Ligand