The cannabinoid receptor 2 is involved in acute rejection of cardiac allografts

Kemter A., Scheu S., Hüser N., Ruland C., Schumak B., Findeiß M., Cheng Z., Assfalg V., Arolt V., Zimmer A., Alferink J.

Abstract

Aims Acute rejection of cardiac allografts is a major risk factor limiting survival of heart transplant recipients. Rejection is triggered by dendritic cell (DC) mediated activation of host T cells, amongst others CD4+ T helper (TH)1- and TH17 cells. The cannabinoid receptor 2 (CB2) is an important modulator of cellular immune responses. However, its role in cardiac allograft rejection has not been studied so far. Main methods Here, we examined the effect of CB2 on cytokine release by mature DCs and its impact on CD4+ T cell differentiation by utilizing in vitro generated bone marrow-derived DCs (BM-DCs) and CD4+ T cells from CB2 knockout (Cnr2-/-) mice. We further assessed the functional role of CB2 in acute allograft rejection using Cnr2-/- mice in a fully major histocompatibility complex-mismatched mouse cardiac transplantation model. Key findings Cardiac allograft rejection was accelerated in Cnr2-/- mice compared to wild type recipients. In vitro stimulation of BM-DCs showed enhanced secretion of the pro-inflammatory cytokines interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF) and the immunomodulatory cytokine TGF-β. Furthermore, secretion of the TH1/TH17 promoting cytokines IL-12 and IL-23 was increased in Cnr2-/- BM-DCs. In addition, Cnr2-/- CD4+ T cells showed an enhanced capacity to differentiate into interferon (IFN)-γ- or IL-17-producing effector cells. Significance These results demonstrate that CB2 modulates in vitro cytokine responses via DCs and directly via its influence on TH1/TH17 differentiation. These findings and the fact that allograft rejection is enhanced in Cnr2-/- mice suggest that CB2 may be a promising therapeutic target in organ transplantation.