Interleukin-17 antagonism inhibits acute but not chronic vascular rejection

Background. Blocking the action of interleukin (IL) 17 with an IL-17 recept or (R):Fc fusion protein inhibits T-cell proliferative responses to alloant igens and prolongs vascularized heart graft survival. In this study, we exa mined whether IL-17 antagonism could suppress the development of chronic re jection. Methods. A 0.6-cm section of C57BL10 (H2(b)) thoracic aorta was transplante d to recipient C3H (H2(k)) abdominal aorta. IL-17R:Fc or control human immu noglobulin G was administered i.p. (500 mug/day) from days 0 to 6 or from d ays 0 to 29. Mice were killed on days 7 or 30. Grafts were examined histolo gically and stained for a-smooth muscle actin (alpha -smA). Antidonor mixed leukocyte reaction, cytotoxic T cell, and alloantibody responses were quan tified. Results. On day 7, control grafts showed mononuclear cell (MNC) infiltratio n, pronounced endothelial damage, and apoptosis of intimal and medial cell compartments. By day 30, there was concentric intimal thickening, accumulat ion of alpha -smA(+) cells, and collagen deposition. Patchy destruction of the elastic membranes and loss of a-smA expression in media were evident. I L-17R:Fc for 6 days decreased MNC infiltration in the intimal. and medial c ompartments at day 7. The endothelium, was preserved (completely or partial ly) in all grafts. The medial compartment showed normal a-smA expression. I rrespective of IL-17R:Fc treatment for either 6 days or continuously, allog rafts harvested at day 30 showed circumferential intimal thickening, with a ccumulation of alpha -smA(+) cells and collagen deposition. There was no ef fect on circulating alloantibody levels. Conclusions. These findings support a role for IL-17 in the immunopathogene sis of acute vascular rejection and demonstrate the potential of IL-17 anta gonism for therapy. By contrast, IL-17 antagonism does not appear to preven t ensuing chronic graft vascular disease, in particular neointimal formatio n.