Abstract 5850: Role of Interleukin-6 and its Crosstalk with AT1R in Acute and Chronic Rejection of Murine Cardiac Allografts
Potential interactions between interleukin (IL)-6 and renin-angiotensin system have been demonstrated in a range of inflammation; however, the roles in alloimmune response have not been fully identified. The present study was designed to investigate the impact of IL-6 blockade and its crosstalk with angiotensin II type 1 receptor (AT1R) on the pathophysiology of cardiac allograft rejection. Fully MHC-mismatched hearts from BALB/c donors were transplanted into C57BL/6 mice. Recipients were treated with either anti-mouse IL-6 receptor antibody (MR16–1: 2 mg/mouse, i.p. on days 0, 3, and 6) or olmesartan, an AT1R antagonist (5 mg/kg, oral, daily). Treatment with MR16–1 inhibited the development of acute rejection, and allograft survival was significantly prolonged (median survival time (MST) was 16.5 days, n= 6 vs. control: 7 days, n= 11, p< 0.01). In recipients treated with MR16–1, alloantibody production was markedly suppressed; and in addition, real-time PCR and immunohistochemistry revealed less AT1R expression in the allografts. Treatment with olmesartan failed to prolong graft survival (MST: 9 days, n= 8); however, olmesartan modestly inhibited intragraft mononuclear cell infiltration. MR16–1 treatment in combination with olmesartan further prolonged graft survival (MST: 21 days, n= 5, p= 0.045), and significantly suppressed intragraft cell infiltration. Chronic rejection was also evaluated at day 60 using a class II-mismatched model between B6.C-H2bm12 and C57BL/6 mice. MR16–1 treatment (0.5 mg/mouse, i.p. twice/week) inhibited chronic allograft rejection, and we observed significantly less graft arteriosclerosis (luminal occlusion of coronary arteries: 59.6+/−6.0% vs. 23.7+/−4.2%, p< 0.001) and reduction of myocardial fibrosis area (46.5+/−4.1% vs. 19.0+/−6.9%, p< 0.001, n= 6 each). IL-6 receptor blockade using MR16–1 prevented both acute and chronic rejection of cardiac allografts, accompanied with a decrease in intragraft expression of AT1R. The synergistic effect of IL-6 blockade and AT1R antagonist suggests that approaches targeting on the crosstalk between IL-6 and AT1R signaling may open potential strategies to manipulate immune responses against cardiac allografts.