Graft-Derived IL-6 Amplifies Proliferation and Survival of Effector T Cells That Drive Alloimmune-Mediated Vascular Rejection.

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.