148: The IL-23/IL-17 axis in human cardiac allograft vasculopathy

Abstract

Purpose: Cardiac Allograft Vasculopathy (CAV) after heart-transplantation is a major factor limiting the long-term patient survival. CAV is characterized by a concentric intima proliferation, which is induced by a mononuclear cell infiltrate (MNC). This process is often compared with a proliferative autoimmune disease in which IL-17 producing T-helper cells (Th17) play a central role. In this study the role of Th17 in the development of CAV was analyzed. Methods and Materials: Coronary arteries (CA) were obtained from CAV patients (n 6) and compared to CA from non-CAV patients (n 5). Q-PCR analysis was performed using a low density array on cDNA prepared from 5 microdissected areas: 1) luminal layer of the intima (LL), 2) smooth muscle cell layer of the intima, 3) tunica media, 4) adventitia (AD), and 5) lymphoid clusters outside the vessel. Genes (50) were selected for Th1/Th2/Th17 characterization. Positive gene expression by Q-PCR analysis was confirmed and localized by in situ hybridization and immunohistochemistry. Results: Tand B-cells were mainly detected in the LL and the AD of CAV and were absent in control CA. Cytokine expression in CAV was generally low, probably due to the immunosuppression. IFN, known to inhibit Th17, was however, significantly expressed, mainly in LL and AD of CAV but not in control CA. TGF, which induces Th17, was detected in both CAV and control CA, and was localized in macrophages. Th1 markers were abundantly present, but Th17 markers such as IL17, IL-23, and IL23R were weakly expressed or absent. Likewise, regulatory T-cells (FoxP3) were not detected in CAV and control CA, and Th2 markers only on a minority of MNC. Conclusions: In autoimmunity, a dichotomy between inducing Th17 and inhibiting regulatory T-cells has been described. In CAV, both are absent. This is suggestive of a different mechanism driving the proliferative response, possibly due to the low cytokine response under immunosuppression. Therefore, we suggest that the Th1-cells, which are predominant in the MNC, are responsible for the direct or indirect induction of the proliferative response.