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


CONCLUSIONS
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.
Raisky
Olivier
O
National Heart and Lung Institute, Imperial College School of Medicine, Harefield Hospital, Harefield, Middlesex, UK.
Spriewald
Bernd M
BM
Morrison
Karen J
KJ
Ensminger
Stephan
S
Mohieddine
Tarek
T
Obadia
Jean Francois
JF
Yacoub
Magdi H
MH
Rose
Marlene L
ML
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017539:Tunica Intima / Q000473:pathology
D019013:CD40 Antigens; D016207:Cytokines; D023201:CD40 Ligand