Published Online
on October 2, 2006

A more recent version of this article appeared on October 10, 2006

This Article Full Text (PDF) All Versions of this Article: 114/15/1599    most recent CIRCULATIONAHA.105.597526v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Loosdregt, J. Articles by de Weger, R. A. Search for Related Content PubMed PubMed Citation Articles by van Loosdregt, J. Articles by de Weger, R. A. Related Collections Other heart failure Coronary circulation Mechanism of atherosclerosis/growth factors Other Vascular biology Growth factors/cytokines Smooth muscle proliferation and differentiation

Submitted on October 25, 2005
Revised on June 7, 2006
Accepted on June 21, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: r.deweger{at}umcutrecht.nl.

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.

Key words: arteriosclerosis • cardiovascular diseases • chemokines • heart failure • immunology • pathology • transplantation

This article has been cited by other articles:

				D. Schmauss and M. Weis Cardiac Allograft Vasculopathy: Recent Developments Circulation, April 22, 2008; 117(16): 2131 - 2141. [Abstract] [Full Text] [PDF]

				A. Lombardi, G. Cantini, E. Piscitelli, S. Gelmini, M. Francalanci, T. Mello, E. Ceni, G. Varano, G. Forti, M. Rotondi, et al. A New Mechanism Involving ERK Contributes to Rosiglitazone Inhibition of Tumor Necrosis Factor-{alpha} and Interferon-{gamma} Inflammatory Effects in Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., April 1, 2008; 28(4): 718 - 724. [Abstract] [Full Text] [PDF]

				S. Arora, P. A. Jenum, P. Aukrust, H. Rollag, A. K. Andreassen, S. Simonsen, E. Gude, A. E. Fiane, O. Geiran, and L. Gullestad Pre-Transplant Toxoplasma gondii Seropositivity Among Heart Transplant Recipients Is Associated With an Increased Risk of All-Cause and Cardiac Mortality J. Am. Coll. Cardiol., November 13, 2007; 50(20): 1967 - 1972. [Abstract] [Full Text] [PDF]

				M. L. Rose Interferon-{gamma} and Intimal Hyperplasia Circ. Res., September 14, 2007; 101(6): 542 - 544. [Full Text] [PDF]

				Y. Wang, Y. Bai, L. Qin, P. Zhang, T. Yi, S. A. Teesdale, L. Zhao, J. S. Pober, and G. Tellides 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., September 14, 2007; 101(6): 560 - 569. [Abstract] [Full Text] [PDF]

				D. M. Brainard, A. M. Tager, J. Misdraji, N. Frahm, M. Lichterfeld, R. Draenert, C. Brander, B. D. Walker, and A. D. Luster Decreased CXCR3+ CD8 T Cells in Advanced Human Immunodeficiency Virus Infection Suggest that a Homing Defect Contributes to Cytotoxic T-Lymphocyte Dysfunction J. Virol., August 15, 2007; 81(16): 8439 - 8450. [Abstract] [Full Text] [PDF]

				G. Tellides and J. S. Pober Interferon-{gamma} Axis in Graft Arteriosclerosis Circ. Res., March 16, 2007; 100(5): 622 - 632. [Abstract] [Full Text] [PDF]

				G. Tellides Th1 Adaptive Immune Responses in Cardiac Graft Arteriosclerosis: Deleterious or Beneficial? Circulation, October 10, 2006; 114(15): 1561 - 1564. [Full Text] [PDF]