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. 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-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.