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(Circulation. 2006;114:1599-1607.)
© 2006 American Heart Association, Inc.

Transplantation

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

Jorg van Loosdregt, MSc; Matthijs F.M. van Oosterhout, MD, PhD; Annette H. Bruggink, MSc; Dick F. van Wichen, BSc; Joyce van Kuik, BSc; Erica de Koning, BSc; Carla C. Baan, PhD; Nicolaas de Jonge, MD, PhD; Frits H.J. Gmelig-Meyling, PhD; Roel A. de Weger, PhD

From the Department of Pathology (J.v.L., M.F.M.v.O., A.H.B., D.F.v.W., J.v.K., E.d.K., R.A.d.W.), Heart Lung Center Utrecht (N.d.J.), and Department of Immunology (F.H.J.G.-M.), University Medical Center Utrecht, Utrecht; and Department of Internal Medicine, Erasmus Medical Center, Rotterdam (C.C.B.), the Netherlands.

Correspondence to Roel de Weger, PhD, Molecular Pathology and Immunopathology, Department of Pathology (H04.312), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA Utrecht, The Netherlands. E-mail r.deweger{at}umcutrecht.nl

Received October 25, 2005; revision received June 7, 2006; accepted June 21, 2006.

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.

Methods and 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- 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- 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.

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