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

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.
Copyright © 2015. Published by Elsevier Inc.