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.
BACKGROUND
Despite improvement in short-term patient survival after heart transplantation (HTx), long-term survival rates have not improved much, mainly because of cardiac allograft vasculopathy (CAV). Cytokines and chemokines are considered to play an important role in CAV development.


RESULTS
We focused on coronary arteries of HTx patients and made an inventory of the infiltrating cells and the expression of cytokines as well as chemokines and chemokine receptors (C+CR) in the different layers of the vessel wall with CAV. Tissue slides were stained for a variety of cell markers (CD3, CD4, CD8, CD20, CD68, CD79a), chemokines (monokine induced by interferon [MIG], interferon-inducible protein 10 [IP-10], interferon-inducible T cell-alpha chemoattractant [ITAC], RANTES [regulated on activation normal T cell expressed and secreted], and fractalkine), and chemokine receptors (CXCR3, CCR5, and CX3CR1). In reference coronary arteries (not transplanted), almost no infiltrating cells were found, and in transplanted hearts with CAV (HTx+CAV), a large number of T cells were observed (CD4:CD8=2:1), mainly localized in the neointima and adventitia. Most of these T cells appeared to be activated (human leukocyte antigen DR positive). Coronary arteries from transplanted hearts without CAV (HTx-CAV), HTx+CAV, and references were also analyzed for cytokine and C+CR mRNA expression with the use of quantitative polymerase chain reaction. Interferon-gamma was highly expressed in HTx+CAV compared with HTx-CAV. Interleukin-4 and interleukin-10 were expressed at the same level in both HTx groups and references. In HTx+CAV, all C+CR, but especially the T-helper 1 (TH1) C+CR, were more abundant than in the HTx-CAV and references. However, TH2 CCR4 expression did not differ significantly between both HTx groups.


CONCLUSIONS
In coronary arteries with CAV, most T cells are CD4+ and express human leukocyte antigen DR. These activated TH cells are mainly memory TH1 cells on the basis of their C+CR profile and cytokine expression.
van Loosdregt
Jorg
J
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands.
van Oosterhout
Matthijs F M
MF
Bruggink
Annette H
AH
van Wichen
Dick F
DF
van Kuik
Joyce
J
de Koning
Erica
E
Baan
Carla C
CC
de Jonge
Nicolaas
N
Gmelig-Meyling
Frits H J
FH
de Weger
Roel A
RA
D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002303:Cardiac Output, Low / Q000601:surgery; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000209:etiology / Q000473:pathology*; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014184:Transplantation, Homologous / Q000009:adverse effects / Q000276:immunology / Q000473:pathology; D017539:Tunica Intima / Q000473:pathology
D018925:Chemokines; D006684:HLA-DR Antigens; D012333:RNA, Messenger; D019707:Receptors, Chemokine