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

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.

Keywords: Cannabinoid receptor 2; Cardiac allografts; Dendritic cells; Endocannabinoids; Graft rejection; Solid organ transplantation; TH1 and TH17 cells.