265.12: NLRP3 inhibition prevented graft infiltration of inflammatory macrophages leading to long-term graft acceptance in mouse heart transplantation.

Le résumé fourni par la source

Background: Inflammasome complexes including NLRP3 play a central role in ischemia-reperfusion injury in transplantation. Aim. To examine the impact of NLRP3 inhibitior on graft preservation and allo-immune responses in organ transplantation. Methods. BALB/c mice were transplanted with C57BL/6 (B6) cardiac allografts. Grafts were stored for 0.5 h or 8 h cold ischemia time (CIT) in heparin saline solution (1%) with or without NLRP3 inhibitor, MCC950 (400 nM). Mice were given 250 μg of CTLA-4 Ig intraperitoneally on day 2 post-transplantation. IFNg-ELIspot assays were performed using splenocytes obtained from mice on day 2 and 10 post-transplantation after coculturing with irradiated donor-strain splenocytes for 24 h. Results: Almost all B6 cardiac allografts were well-functioning when transplanted into BALB/c mice immediately after harvesting (0.5 h CIT). Meanwhile, 30% of primary graft non-function was observed after 8 h CIT (n=20, *P=0.027 vs. 0.5h). Treatment with MCC950 during 8 h CIT significantly reduced incidence of primary non-function (n=25, 4.2%, *P=0.0353). Nonetheless, MCC950 during cold preservation alone had no effect on the survival time of allograft (solid circles and solid line, Fig. 1). The CTLA-4 Ig treatment on day 2 posttransplantation efficiently prolonged 4 of 5 B6 allografts survival time >100 days in 0.5 h CIT (solid triangles and dotted line, Fig. 1) but not in 8 h CIT (MST=22.5 days, n=6, empty inverted triangles and solid line, Fig. 1). Of note, addition of MCC950 during 8 h CIT together with CTLA-4 Ig treatment on day 2 posttransplantation significantly prolonged a graft survival time (empty circles and solid line, Fig. 1).A significant lower IFNg production of splenocytes obtained from BALB/c mice treated with CTLA-4 Ig on day 10 post-transplantation was observed when allografts were treated with MCC950 during 8 h CIT (Fig. 2).In addition, MCC950 significantly inhibited graft infiltration of CD11bhigh F4/80+ macrophages with inflammatory phenotype; CCR2+ CD86+ Ly6C+ MHC class II- on day 2 post-transplantation (Fig. 3). Furthermore, the inhibition of graft infiltration of inflammatory macrophages by anti-CCR2 antagonist significantly prolonged graft survival time in 8 h CIT (4 of 5 allografts survival time >100 days, n=5, *P=0.0316 vs. untreated 8 h CIT). Conclusion: Inhibition of NLRP3 activation of the graft with prolonged CIT prevented inflammatory macrophages infiltration into the graft leading to long-term graft acceptance. It could be a promising treatment strategy for inducing an immune tolerance in organ transplantation.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.