Heart transplantation is potentially the only viable option for patients with end-stage heart failure. Despite advances in immunosuppressive therapies, cardiac allograft chronic rejection is a significant problem. Graft loss is primarily due to tissue damage mediated by immune responses. Cell death and organ rejection can occur as an active molecular process through apoptotic and necrotic pathways. We now recognize that cell death may also ensue through a newly described form of programmed necrotic cell death, termed necroptosis, which involves receptor-interacting protein kinase (RIPK) 1 and 3. In this study, we aim to establish the role of RIPK3 in CD4⁺ T cell-mediated chronic cardiac allograft rejection using the single MHC class II mismatch C57BL/6 (H-2^b; B6) or B6.129R1-RIPK3^tm1Vmd (H-2^b; RIPK3^-/-) to B6.C-H-2^Bm12 (H2-Ab1^bm12; Bm12) transplantation mouse model.

Our studies show that the CD4⁺ T-cell-mediated heart graft rejection is inhibited in RIPK3-deficient donor grafts with reduced cellular infiltration and endothelial cell damage compared with wild type grafts. Allo-reactive CD4⁺ T-cells produce tumor necrosis factor α (TNF-α) and express fas ligand (FasL) and granzyme B. Interestingly, TNF-α-mediated necroptosis was triggered in vitro by inhibition of apoptosis in wild type but not in RIPK3^-/- microvascular endothelial cells. Furthermore, CD4⁺ T-cell induced necroptotic and apoptotic cell death via FasL-Fas interaction and granzyme B. RIPK3^-/- endothelial cells were resistant necroptotic cell death. In conclusion, cytotoxic CD4⁺ T-cell-mediated endothelial cell necroptotic and apoptotic death is dependent on TNFα, FasL, and granzyme B. Loss of RIPK3 in the graft attenuates alloimmune responses and prolonged heart graft survival. Our study indicates that targeting RIPK mediated necroptosis may be an important therapeutic strategy in organ transplantation.

CITATION INFORMATION: Kwok C, Montwill N, Pavlosky A, Haig A, Huang X.-Y, Jevnikar A, Zhang Z.-X. Necroptosis Is Involved in CD4⁺ T-Cell Mediated Microvascular Endothelial Cell Death and Chronic Cardiac Allograft Rejection. Am J Transplant. 2016;16 (suppl 3).

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