Session Time: 3:15pm-4:45pm
Presentation Time: 3:27pm-3:39pm
*Purpose: Bromodomain and extra-terminal domain (BET) proteins are a family of proteins that function as epigenetic readers that regulate transcriptional activities of target genes. BET proteins bind acetylated H3K27 and usually organize super enhancer formation that critically determines cell fate decisions including immune cells. In the present studies, we examined whether and how targeting BET proteins using a chemical inhibitor JQ1 would regulate transplant survival in mouse heart transplant model.
*Methods: A BALB/c to C57BL/6 (B6) heart transplantation model was adopted to evaluate the function of BET proteins inhibitor JQ1. Graft-infiltrating immune cells were isolated and analyzed. Mechanisms of tolerance were investigated using bone marrow-derived macrophages (BMDMs) in vitro.
*Results: Using a fully MHC mismatched heart transplant model (BALB/c to B6), we observed that treatment of recipient mice with JQ1 did not affect acute allograft rejection. However, when combined with CTLA4-Ig,JQ1 induced long-term allograft survival (>100 days) without histological signs of chronic rejection, which was in stark contrast to CTLA4-Ig treated mice (MST~40 days).Analysis of graft-infiltrating cells showed that the most striking effects of JQ1 treatment was the inhibition of M2 type macrophages. Furthermore, in vitro experiments using BMDMs showed that JQ1 suppressed the induction of Arg-1, a classical M2 marker, suggesting that JQ1 impaired M2 polarization. Immunofluorescence staining and RNA sequencing studies on M2 cells induced with or without JQ1 also supported this conclusion. RNA sequencing showed that the expression of M2-associated transcription factors KLF4, KLF9, IRF4 and ppar-γ was downregulated after JQ1 treatment. Studies using gene knockout mice showed that the expression levels of IRF4, KLF4, ppar-γ, RelB had little effects on Arg-1 induction, but the nuclear localization of p-STAT6 was profoundly reduced after JQ1 treatment. Additionally, ChIP-qPCR showed that STAT6 binding at the Arg-1 locus was reduced after JQ1 treatment, and the expression of Arg-1 eRNA was also abrogated after JQ1 treatment.
*Conclusions: These novel data suggest that BET protein inhibition is a new strategy for preventing chronic allograft rejection. A possible mechanism for promoting graft survival is suppression of M2 macrophage polarization.
To cite this abstract in AMA style:Wang G, Xiao X, Dou Y, Kong G, Li X. Novel Approaches in Targeting Chromatin Modifiers in the Induction of Transplant Tolerance [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/novel-approaches-in-targeting-chromatin-modifiers-in-the-induction-of-transplant-tolerance/. Accessed May 7, 2021.
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