Impact of hyperlipidemia on alloimmunity

Abstract

Purpose of Review Hyperlipidemia is a co-morbidity affecting a significant number of transplant patients despite treatment with cholesterol lowering drugs. Recently it has been shown that hyperlipidemia can significantly alter T cell responses to cardiac allografts in mice, and graft rejection is accelerated in dyslipidemic mice. Here we review recent advances in our understanding of hyperlipidemia in graft rejection. Recent Findings Hyperlipidemic mice have significant increases in serum levels of pro-inflammatory cytokines, and neutralization of IL-17 slows graft rejection, suggesting that IL-17 production by Th17 cells was necessary but not sufficient for rejection. Hyperlipidemia also causes an increase in alloreactive T cell responses prior to antigen exposure. Analysis of peripheral tolerance mechanisms indicated that this was at least in part due to alterations in FoxP3+ T cells that led to reduced Treg function and the expansion of FoxP3+ CD4 T cells expressing low levels of CD25. Functionally, alterations in Treg function prevented the ability to induce operational tolerance to fully allogeneic heart transplants through costimulatory-molecule blockade, a strategy that requires Tregs. Summary These findings highlight the importance of considering the contribution of inflammatory co-morbidities to cardiac allograft rejection, and point to the potential importance of managing hyperlipidemia in the transplant population.

The role of IL-6 in hyperlipidemia-induced accelerated rejection

“…Given the systemic effects of hyperlipidemia that promote inflammation, we examined how hyperlipidemia affects transplant outcome. We have shown that hyperlipidemia promotes accelerated rejection of vascularized cardiac allografts 16–18 . Hyperlipidemia‐induced accelerated rejection is associated with an increase in anti‐donor Th1 and Th17 responses as well as changes in Tregs and increases in serum concentrations of inflammatory cytokines 16 …”

“…We have shown that hyperlipidemia promotes accelerated rejection of vascularized cardiac allografts. [16][17][18] Hyperlipidemia-induced accelerated rejection is associated with an increase in anti-donor Th1 and Th17 responses as well as changes in Tregs and increases in serum concentrations of inflammatory cytokines. 16 Systemic changes induced by hyperlipidemia include increased serum levels of IL-6.…”