Interleukin-17 antagonism inhibits acute but not chronic vascular rejection.
BACKGROUND
Blocking the action of interleukin (IL) 17 with an IL-17 receptor (R):Fc fusion protein inhibits T-cell proliferative responses to alloantigens and prolongs vascularized heart graft survival. In this study, we examined whether IL-17 antagonism could suppress the development of chronic rejection.


METHODS
A 0.6-cm section of C57BL10 (H2b) thoracic aorta was transplanted to recipient C3H (H2k) abdominal aorta. IL-17R:Fc or control human immunoglobulin G was administered i.p. (500 microg/day) from days 0 to 6 or from days 0 to 29. Mice were killed on days 7 or 30. Grafts were examined histologically and stained for alpha-smooth muscle actin (alpha-smA). Antidonor mixed leukocyte reaction, cytotoxic T cell, and alloantibody responses were quantified.


RESULTS
On day 7, control grafts showed mononuclear cell (MNC) infiltration, pronounced endothelial damage, and apoptosis of intimal and medial cell compartments. By day 30, there was concentric intimal thickening, accumulation of alpha-smA+ cells, and collagen deposition. Patchy destruction of the elastic membranes and loss of alpha-smA expression in media were evident. IL-17R:Fc for 6 days decreased MNC infiltration in the intimal and medial compartments at day 7. The endothelium was preserved (completely or partially) in all grafts. The medial compartment showed normal alpha-smA expression. Irrespective of IL-17R:Fc treatment for either 6 days or continuously, allografts harvested at day 30 showed circumferential intimal thickening, with accumulation of alpha-smA+ cells and collagen deposition. There was no effect on circulating alloantibody levels.


CONCLUSIONS
These findings support a role for IL-17 in the immunopathogenesis of acute vascular rejection and demonstrate the potential of IL-17 antagonism for therapy. By contrast, IL-17 antagonism does not appear to prevent ensuing chronic graft vascular disease, in particular neointimal formation.
Tang
J L
JL
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, W1544 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213, USA. thomsonaw@msx.upmc.edu.
Subbotin
V M
VM
Antonysamy
M A
MA
Troutt
A B
AB
Rao
A S
AS
Thomson
A W
AW
D000208:Acute Disease; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D001013:Aorta, Thoracic / Q000601:surgery / Q000637:transplantation*; D002908:Chronic Disease; D003165:Complement System Proteins / Q000276:immunology; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000276:immunology*; D007518:Isoantibodies / Q000097:blood; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014184:Transplantation, Homologous / Q000276:immunology*
D007074:Immunoglobulin G; D020381:Interleukin-17; D007518:Isoantibodies; D018123:Receptors, Interleukin; D011993:Recombinant Fusion Proteins; C118179:rmIL-17R:huFc; D003165:Complement System Proteins