Non-HLA Antibodies Targeting Vascular Receptors Enhance Alloimmune Response and Microvasculopathy After Heart Transplantation

Background. Non-human leukocyte antigen antibodies (Abs) targeting vascular receptors are implicated in the pathogenesis of renal allograft vascular rejection and in progressive vasculopathy in patients with systemic sclerosis. Methods. We prospectively tested in 30 heart transplant recipients the impact of Abs directed against endothelin-1 type A (ETAR) and angiotensin II type 1 receptors (AT(1)R, cell-enzyme-linked immunosorbent assay) at time of transplantation and during the first posttransplantation year on cellular and Ab-mediated rejection (immunohistochemistry, C3d, and immunoglobulins) and microvasculopathy in endomyocardial biopsy. Results. Cellular rejection, Ab-mediated rejection, and microvasculopathy was found in 40% and 13%, 57% and 18%, and 37% and 40% of biopsies at 1 month and 1 year posttransplantation, respectively. Maximum levels of AT(1)R and ETAR Abs were higher in patients with cellular (16.5 +/- 2.6 vs. 9.4 +/- 1.3; P=0.021 and 16.5 +/- 2.5 vs. 9.9 +/- 1.9; P=0.041) and Ab-mediated rejection (19.0 +/- 2.6 vs. 10.0 +/- 1.3; P=0.004 and 19.4 +/- 2.7 vs. 9.0 +/- 1.7; P=0.002), as compared with patients who had no rejection. Patients with elevated AT(1)R Abs (53% [16/30]) or ETAR Abs (50% [15/30]; pretransplantation prognostic rejection cutoff >16.5 U/L) presented more often with microvasculopathy (both, 67% vs. 23%; P=0.048) than patients without. Conclusions. Elevated levels of AT(1)R and ETAR Abs are associated with cellular and Ab-mediated rejection and early onset of microvasculopathy and should be routinely monitored after heart transplantation.