CCR4‐deficient mice show prolonged graft survival in a chronic cardiac transplant rejection model

Abstract

Chronic graft rejection mediated by cellular immune responses still poses a serious clinical problem in transplant surgery. Chemokines coordinate the recruitment of leukocytes in inflammatory and immune responses. Their precise functions in the rejection of allografts are still ill defined. This study investigates the role of chemokine receptor 4 (CCR4) in acute and chronic cardiac allograft rejection in mice. Allogeneic hearts were transplanted into CCR4 deficient (CCR4 -/-) and control recipients. Reverse transcription-PCR showed transcription of macrophage-derived chemokine and thymus and activation-regulated chemokine, the cognate chemokine ligands of CCR4, within the graft. Compared to wild-type controls, acute allograft rejection in CCR4 -/-recipients was only slightly prolonged. In contrast, in a gallium nitrate chronic cardiac allograft rejection model, cardiac graft survival was significantly prolonged in CCR4 -/-recipients. A relative increase in the percentage of graft infiltrating CD8 + T cells in CCR4 -/-recipients was observed 30 days after transplantation and was accompanied by a decrease in CD4 + T cells. Moreover, the percentage of NK1.1 + CD3 + graft-infiltrating cells was significantly reduced on day 5 and day 30 post transplantation. These findings indicate that CCR4 is involved in the recruitment of NK1.1 + CD3 + cells into cardiac allografts and clearly establish an important and novel role for CCR4 in chronic graft rejection.

Immunosuppressive Effects of CCL17 on Pulmonary Antifungal Responses during Pulmonary Invasive Aspergillosis

“…Studies previous to ours suggested that the innate immune response in CCR4 Ϫ/Ϫ mice was altered in that these mice were dramatically less susceptible to the development of lipopolysaccharide-induced endotoxic shock (22). More recently, CCR4 Ϫ/Ϫ mice showed prolonged cardiac allograft survival compared with their wild-type counterparts (33). Given that previous reports have suggested that CCL17 can bind and signal through CCR8 (8,36), the development of invasive pulmonary aspergillosis was also examined in CCR8 Ϫ/Ϫ mice.…”

CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T cell homeostasis in mice

“…In contrast, Treg recruitment was less pronounced and not altered in Ccl17 E/E Apoe -/-mice. Nevertheless, the inflammatory recruit- (25), lymphocyte and CD4 + T cell recruitment was unaltered in various in vivo models, e.g., OVA-induced airway inflammation, cardiac allograft rejection, and skin inflammation related to atopic dermatitis in Ccr4 -/-mice (36)(37)(38). Notably, we found increased Treg accumulation in aortas of Ccl17 E/E Apoe -/-mice and in LNs of Ccl17-deficient mice.…”

Effector Mechanisms of Rejection

“…Inhibition of CCR4 and its ligands led to an increase in heart graft survival associated with a decreased in DC/T-cell interactions and an inhibition of monocytes and NK cells present in the graft (Alferink et al 2003;Huser et al 2005). Last, CCR7 is known to be involved in the localization of both DCs and T cells in the T-cell-rich zones of the LNs, indicating a role for CCR7 in T-cell homing and priming (Hopken et al 2004).…”