title: Graft-Derived IL-6 Amplifies Proliferation and Survival of Effector T Cells That Drive Alloimmune-Mediated Vascular Rejection.
abstract: BACKGROUND
  IL-6 is an inflammatory cytokine that controls effector T cell responses but the mechanisms by which it controls allogeneic immune responses and vascular rejection that leads to transplant arteriosclerosis (TA) are poorly understood.
  
  
  METHODS
  We have examined the mechanism by which IL-6 contributes to the pathogenesis of vascular rejection and TA using a murine aortic interposition model of vascular rejection.
  
  
  RESULTS
  The absence of IL-6 production from artery graft cells reduced the development of vascular rejection and arteriosclerotic thickening. There was no apparent effect of donor-derived IL-6 on endothelial cell integrity or on the intimal accumulation of smooth muscle cells, macrophages, and anti-donor antibodies. However, reduced vascular pathology in IL-6 artery grafts was accompanied by a significant reduction in the accumulation of CD4 and CD8 T cells. Further, the absence of graft-derived IL-6 resulted in a significant decrease in the activation and proliferation of alloreactive CD4 and CD8 T cells after transplantation as well as in a marked increase in cell death of effector T cells. Alloreactive effector T cells that expanded in the absence of IL-6 were also more susceptible to Fas-mediated activation-induced cell death in vitro. Finally, systemic neutralization of IL-6R did not reduce arteriosclerotic thickening but reduced endothelial integrity in allograft arteries, indicating differential effects of specific elimination of IL-6 in graft cells and systemic IL-6 neutralization.
  
  
  CONCLUSIONS
  Donor-derived IL-6 amplifies the expansion of allogeneic T cell responses that cause vascular rejection and TA by increasing T cell proliferation and preventing Fas-mediated T cell death.
authors.affiliation: 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: von Rossum
authors.forename: Kevin
authors.initials: K
authors.lastname: Rey
authors.forename: Winnie
authors.initials: W
authors.lastname: Enns
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Manku
authors.forename: Rajan
authors.initials: R
authors.lastname: Cheema
authors.forename: Grace E
authors.initials: GE
authors.lastname: MacEwan
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Choy
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D006084:Graft Rejection / Q000209:etiology*; D016027:Heart Transplantation / Q000009:adverse effects*; D015850:Interleukin-6 / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019947:Receptors, Interleukin-6 / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015850:Interleukin-6; D007519:Isoantigens; D019947:Receptors, Interleukin-6