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


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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
Andrea M
AM
Kemter
Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
Stefanie
S
Scheu
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Norbert
N
Hüser
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
Christina
C
Ruland
Institute of Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany.
Beatrix
B
Schumak
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
Matthias
M
Findeiß
Department of General Surgery, The Affiliated Zhongda Hospital, Southeast University, Nanjing 210009, China.
Zhangjun
Z
Cheng
Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Volker
V
Assfalg
Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany.
Volker
V
Arolt
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
Andreas
A
Zimmer
Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University of Münster, Münster, Germany; Cells-in-Motion Cluster of Excellence EXC 1003, University of Münster, Münster , Germany. Electronic address: Judith.alferink@ukmuenster.de.
Judith
J
Alferink
D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D006084:Graft Rejection / Q000503:physiopathology*; D016027:Heart Transplantation; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics
D016207:Cytokines; D043884:Receptor, Cannabinoid, CB1
Cannabinoid receptor 2; Cardiac allografts; Dendritic cells; Endocannabinoids; Graft rejection; Solid organ transplantation; TH1 and TH17 cells