Hyperlipidemia Promotes Anti-Donor Th17 Responses That Accelerate Allograft Rejection.

Area of Science:

• Immunology
• Transplantation Biology
• Cardiovascular Research

Background:

• Hyperlipidemia affects 95% of organ transplant recipients.
• The impact of hyperlipidemia on allograft rejection remains understudied.

Purpose of the Study:

• To investigate the effect of hyperlipidemia on organ allograft rejection.
• To elucidate the mechanisms underlying hyperlipidemia-induced accelerated rejection.

Main Methods:

• Induction of hyperlipidemia in a mouse cardiac allograft model.
• Analysis of T cell infiltrates, cytokine levels (IL-2, IL-6, IL-17), and Th17 cell populations.
• Intervention with IL-17 neutralization or genetic ablation.
• Ex vivo analysis of alloreactive T cell frequencies.

Main Results:

• Hyperlipidemia significantly accelerated cardiac allograft rejection.
• Accelerated rejection was linked to aggressive T cell infiltration, tissue damage, and elevated pro-inflammatory cytokines, notably IL-17.
• Hyperlipidemic mice exhibited increased peripheral Th17 cells and IL-17-producing T cells in allografts.
• IL-17 neutralization or ablation prolonged allograft survival in hyperlipidemic recipients.
• Hyperlipidemia increased the frequency of donor-reactive IL-17-producing T cells prior to antigen exposure.

Conclusions:

• Hyperlipidemia promotes accelerated organ allograft rejection.
• This effect is mediated by a shift towards Th17-biased anti-donor immune responses.
• IL-17 plays a critical role in hyperlipidemia-associated allograft rejection.
• Hyperlipidemia can pre-condition T cells to promote Th17 responses upon antigen exposure.