Date: Tuesday, June 4, 2019
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall C & D
*Purpose: Prolonged cold ischemic storage (CIS) of murine cardiac allografts causes complement dependent, CTLA4Ig-resistant rejection that is associated with 48h post-transplant elevations in serum levels of TNFα and intragraft RIPK3 positivity (marker of necroptosis). Because TNFα can induce apoptosis and necroptosis we tested the role of these cell death pathways in this system.
*Methods: While CIS B6 cardiac allografts were rejected by day 30 in CTLA4Ig treated BALB/c recipients, peritransplant administration of anti-TNFα mAb prolonged survival to >70 days, as did absence of donor TNFR2, donor RIPK1 (no apoptosis/necroptosis) or RIPK3 (no necroptosis), together supporting a pathogenic role for TNFα/TNFR2-dependent necroptosis in CTLA4Ig-resistant rejection (all conditions n=4-6, p<0.05 compared to WT CIS donors).
*Results: Sharpin (shrp) is required for ubiquitinylation of RIPK1 which in turn prevents apoptosis/necroptosis, and its absence increases susceptibility to cell death. As anticipated CIS B6 Shrp-/- allografts underwent accelerated rejection in CTLA4Ig-treated BALB/c recipients (MST 13d), but were accepted in BALB/c scid and syngeneic B6 hosts, indicating that donor reactive T cells and an increased susceptibility to cell death synergize to cause graft failure. Analyses of recipient immune responses in CTLA4Ig-treated BALB/c recipients of CIS B6 vs Shrp-/- hearts revealed no differences in donor reactive splenic or graft infiltrating T cells, eliminating the possibility that necroptosis increases T cell priming. We next tested whether primed donor-reactive T cells more efficiently reject an allograft when necroptosis pathways are activated by adoptively transferring equal numbers of donor reactive CD8+ T cells (obtained from untreated BALB/c recipients of B6 hearts) into BALB/c scid recipients of CIS B6 or Shrp-/- hearts. Remarkably, the Shrp-/- grafts were rejected significantly faster than control grafts (MST 21d vs >60d, n=2, p<0.05): induction of allograft necroptosis facilitated the ability of donor reactive T cells to destroy the organ, independent of T cell frequency.
*Conclusions: The results newly highlight the interaction between initiation of intragraft cell death pathways and T cell dependent effector functions, or necro-inflammation, and suggest that inhibiting cell death within the allograft could improve outcomes independent of immunosuppressing donor-reactive T cells.
To cite this abstract in AMA style:Chun N, Ang R, Horwitz J, Fairchild R, III WBaldwin, Ting A, Heeger PS. Prolonged Cold Ischemic Storage Induces Allograft Necro-Inflammation That Increases Graft Susceptibility to T Cell Mediated Rejection [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/prolonged-cold-ischemic-storage-induces-allograft-necro-inflammation-that-increases-graft-susceptibility-to-t-cell-mediated-rejection/. Accessed September 22, 2019.
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