Peri-Transplant VLA-4 Blockade Inhibits Endogenous Memory CD8 T Cell Infiltration into High Risk Cardiac Allografts and CTLA-4Ig Resistant Rejection.
Am J Transplant. 2018 Oct 29;:
Authors: Iida S, Miyairi S, Su CA, Abe T, Abe R, Tanabe K, Dvorina N, Baldwin WM, Fairchild RL
Recipient endogenous memory CD8 T cells expressing reactivity to donor class I MHC infiltrate MHC-mismatched cardiac allografts within 24 hours after reperfusion and express effector functions mediating graft injury. The current study tested the efficacy of VLA-4 blockade to inhibit endogenous memory CD8 T cell infiltration into cardiac allografts and attenuate early post-transplant inflammation. Peri-transplant anti-VLA-4 mAb given to C57BL6 (H-2b ) recipients of AJ (H-2a ) heart allografts completely inhibited endogenous memory CD4 and CD8 T cell infiltration with significant decreases in macrophage, but not neutrophil, infiltration into allografts subjected to either minimal or prolonged cold ischemic storage (CIS) prior to transplant, reduced intra-allograft IFN-γ-induced gene expression and prolonged survival of allografts subjected to prolonged CIS in CTLA-4Ig treated recipients. Anti-VLA-4 mAb also inhibited priming of donor-specific T cells producing IFN-γ until at least day 7 post-transplant. Peri-transplant anti-VLA plus anti-CD154 mAb treatment similarly prolonged survival of allografts subjected to minimal or increased CIS prior to transplant. Overall, these data indicate that peri-transplant anti-VLA-4 mAb inhibits early infiltration memory CD8 T cell infiltration into allografts with a marked reduction in early graft inflammation suggesting an effective strategy to attenuate negative effects of heterologous alloimmunity in recipients of higher risk grafts. This article is protected by copyright. All rights reserved.
PMID: 30372587 [PubMed – as supplied by publisher]