Heme oxygenase-1 modulates CD62E-dependent endothelial cellmonocyte interactions and mitigates HLA-1 induced transplant vasculopathy in mice

Laura Schuster ¹ Marcin Zaradzki ¹ Henrike Janssen ¹ Nadia Gallenstein ¹ Melanie Wickert ¹ Ilse Hofmann ² Markus Weigand ¹ Stephan Immenschuh ³ Jan Larmann ^1*

• ¹ Heidelberg University Hospital, Heidelberg, Germany
• ² German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg, Germany
• ³ Hannover Medical School, Hanover, Lower Saxony, Germany

The main risk factor for developing transplant vasculopathy (TV) after solid organ transplantation is de novo production of donor-specific antibodies (DSA) binding to endothelial cells (EC) within the graft´s vasculature. Diverse leukocyte populations recruited into the vessel wall via activated ECs contribute to vascular inflammation. Subsequent smooth muscle cell proliferation results in intima hyperplasia, the pathophysiological correlate of TV. We demonstrated that incubating aortic EC with anti-HLA I antibodies led to increased monocyte adhesion to and transmigration across an EC monolayer. Both occurred in a CD62E-dependent fashion and were sensitive towards anti-inflammatory enzyme HO-1 modulation. Using a murine heterotopic aortic transplantation model, we demonstrated that anti-MHC I antibodyinduced TV is ameliorated by pharmacologically induced HO-1 and the application of anti-CD62E antibodies results in a deceleration of developing TV. HO-1 modulation is a promising therapeutic approach to prevent leukocyte recruitment and subsequent intima hyperplasia in TV and thus precludes organ failure.