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A. Li et al.
BMI1 contributes to ISC self-renewal, which is co-regu- lated by the Wnt pathway and Notch. The interaction between BMI1 and the Wnt pathway in regulating stem cell self-renewal has been validated in a separate study.86
Yeste et al. noted that STAT3 regulates Il22 promoter accessibility.87 When STAT3-deficient CD4+ T cells were activated in the presence of IL-21, which normally induces Il22 transcription, IL-22 production was signifi- cantly decreased. STAT3-deficient cells also showed decreases in H3 and H4 acetylation, decreases in H3K4me3 and increases in H3K9me3 and H3K27me3 at the Il22 promoter. This could involve a number of epige- netic regulators, including histone methyltransferases (e.g., G9A, SUV39H1, EZH2) and enzymes that modify histone acetylation.87
Recent studies have also implicated the microbiome in aGvHD development and exacerbation. The inflammatory conditions associated with aGvHD, as well as pre-trans- plant preparatory regimens, can harm commensal bacteria populations and compromise the normal functioning of gastrointestinal cells, which in turn result in more severe aGvHD.88-90 For instance, aGvHD inflammation was associ- ated with a loss of SCFA-producing bacteria in the Clostridiales order in both humans and mice.89 Mathewson et al. showed that the levels of the HDAC inhibitor butyrate in IEC were significantly decreased after exposure to allo-HSCT inflammation; this led to decreased histone H4 acetylation and decreased expression of the butyrate transporter and receptor, SLC5A8 and GPR43, respectively, in IEC.90 Increasing intragastric butyrate levels restored H4 acetylation, decreased GvHD severity and improved IEC junction integrity.90 Butyrate treatment was also associated with significantly less IEC apoptosis; among other effects, treatment led to lower expression of pro-apoptotic pro- teins, higher expression of the anti-apoptotic protein BCL- 2 and higher expression of junctional proteins occludin and JAM.90 The promoter regions of Bcl220 (encoding BCL-2) and Fllr (encoding JAM) were noted to be directly associat- ed with H4 acetylation.90 Though the study did not discuss these changes’ impact on recipient physiology, it is plausi- ble that increased IEC junction integrity and decreased apoptosis prevented immune cell infiltration and PAMP/DAMP from escaping the gut, reducing the severity of the aGvHD.
Deeper examination of this aspect of aGvHD biology
and its associated pathways is crucial because it repre- sents a less commonly pursued paradigm in aGvHD treat- ment: fostering recovery of damaged tissues (Figure 1).91
Pharmacological modulation of acute graft-versus-host disease by targeting epigenetic pathways
Development of epigenetic therapy is a particularly active area of cancer research because of such therapies’ potential to selectively target chromatin-modifying enzyme-mediated disease mechanisms.16 Epigenetic ther- apy may produce fewer adverse effects than conventional cytotoxic chemotherapies and may influence response to immunotherapy in various cancers. This logic applies to the search for drugs which modify epigenetic mecha- nisms controlling alloreactive T-cell responses to reduce aGvHD while preserving graft-versus-leukemia activity (Table 2).
HDAC inhibitors
In two clinical trials, patients receiving related and unrelated donor HSCT were treated with the pan-HDAC inhibitor vorinostat (SAHA) after myeloablative condi- tioning to determine the drug’s efficacy at preventing aGvHD. Clinical trials showed a cumulative incidence of grade II-IV aGvHD of 22% by day 100.92,93 Correlative tests on vorinostat-treated patients’ blood samples showed a significant reduction in IL-6.93 Overall, treat- ment with vorinostat was deemed a safe and efficacious strategy for preventing GvHD. Treatment with the pan- HDAC inhibitor panobinostat, in conjunction with corti- costeroids, was also recently investigated for the mitiga- tion of ongoing GvHD.94 Treatment had an approximate- ly 40% response rate, and these responses were noted across grades II and III GvHD in different organ systems. The results are inconclusive because the trial lacked suffi- cient power, but are nevertheless promising.94
DNMTinhibitors
Clinically, Aza and decitabine have been used in the con- text of allo-HSCT for the express purpose of reducing the disease burden before transplantation and as maintenance
Table 2. Selected clinical trials of epigenetic inhibitors in acute graft-versus-host disease.
Drug
Vorinostat (SAHA)
Panobinostat
5-Azacytidine
Main Conclusion
HDAC inhibition with vorinostat in combination with standard prophylaxis resulted in reduced incidence of severe aGvHD. Phase I/II trial.92
HDAC inhibition with vorinostat was safe and efficacious in unrelated donor allo-HSCT patients receiving myeloablative conditioning and methotrexate. Results showed a low cumulative incidence of severe aGvHD. Phase II trial.93
HDAC inhibition with panobinostat in addition to glucocorticoids as primary therapy for aGvHD was deemed safe.
However, the study did not have sufficient power to address efficacy. Phase I/II trial.94
DMNT inhibition by Aza after donor lymphocyte infusion as salvage therapy was well tolerated and no patients developed grade III-IV aGvHD. Phase I trial.95
DMNT inhibition by Aza after allogenic stem cell transplantation increased circulating Treg in patients.
Phase I/II trials.96
SAHA: suberoylanilide hydroxamic acid; HDAC: histone deacetylase; aGVHD: acute graft-versus-host-disease; allo-HSCT: allogeneic hematopoietic stem cell transplantation; Aza: 5-azacytidine; DNMT: DNA methyltransferase; Treg: regulatory T cell
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haematologica | 2020; 105(11)