Necroptosis Is Involved in CD4+T Cell-Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection

作者：Kwok Cecilia; Pavlosky Alexander; Lian Dameng; Jiang Jifu; Huang Xuyan; Yin Ziqin; Liu Weihua; Haig Aaron; Jevnikar Anthony M^*; Zhang Zhu Xu^*

来源：Transplantation, 2017, 101(9): 2026-2037.

DOI：10.1097/TP.0000000000001578

Background Despite advances in immunosuppressive therapies, the rate of chronic transplant loss remains substantial. Organ injury involves various forms of cell death including apoptosis and necrosis. We now recognize that early injury of cardiac transplants involves a newly described form of programmed necrotic cell death, termed necroptosis. Because this involves receptor-interacting protein (RIP) kinase 1/3, this study aimed to establish the role of RIP3 in chronic cardiac allograft rejection.
Methods We used major histocompatibility complex class II mismatched C57BL/6N (H-2(b); B6) or B6.RIP3(-/-) (H-2(b); RIP3(-/-)) mice to B6.C-H-2(bm12) (H2-Ab1(bm12); bm12) mouse cardiac transplantation. Microvascular endothelial cells (MVEC) were developed from B6 and RIP3(-/-) cardiac grafts.
Result CD4(+) T cell-mediated cardiac graft rejection is inhibited using RIP3 deficient donor grafts, with reduced cellular infiltration and vasculopathy compared with wild type cardiac grafts. Alloreactive CD4(+) T cell-mediated MVEC death involves TNF, Fas ligand (FasL) and granzyme B. Although necroptosis and release of danger molecule high-mobility group box 1 are eliminated by the absence of RIP3, CD4(+) T cells had attenuated MVEC death through granzyme B and FasL.
Conclusions CD4(+) T cell-mediated MVEC death involves in TNF, FasL and granzyme B. Necroptotic cell death and release of the danger molecule may promote inflammatory responses and transplant rejection. Although loss of RIP3 does not eliminate alloimmune responses, chronic graft injury is reduced. RIP3 is an important therapeutic target but additional granzyme and caspases inhibition is required for sufficiently improving long-term graft survival.

• 出版日期2017-9