Publications

A recent approach for limiting production of pro-inflammatory cytokines has been to target bromodomain and extra-terminal (BET) proteins. These epigenetic readers of histone acetylation regulate transcription of genes involved in inflammation, cardiovascular disease, and cancer. Development of BET inhibitors (BETi) has generated enormous interest for their therapeutic potential. Because inflammatory signals and donor T cells promote graft-versus-host disease (GVHD), regulating both pathways could be effective to abrogate this disorder. The objective of the present study was to identify a BETi which did not interfere with CD4FoxP3 regulatory T cell (Treg) expansion and function to utilize together with Tregs following allogeneic hematopoietic stem cell transplantation (aHSCT) to ameliorate GVHD. We have reported that Tregs can be markedly expanded and selectively activated with increased functional capacity by targeting TNFRSF25 and CD25 with TL1A-Ig and low dose IL-2, respectively. Here, mice were treated over 7 days (TL1A-Ig + IL-2) together with BETi. We found that the BETi EP11313 did not decrease frequency/numbers or phenotype of expanded Tregs as well as effector molecules, such as IL-10 and TGF-β. However, BETi JQ1 interfered with Treg expansion and altered subset distribution and phenotype. Notably, in Treg expanded mice, EP11313 diminished tnfa and ifng but not il-2 RNA levels. Remarkably, Treg pSTAT5 expression was not affected by EP11313 supporting the notion that Treg IL-2 signaling remained intact. MHC-mismatched aHSCT (B6 → BALB/c) was performed using expanded donor Tregs with or without EP11313 short-term treatment in the recipient. Early post-transplant, improvement in the splenic and LN CD4/CD8 ratio along with fewer effector cells and high Treg levels in aHSCT recipients treated with expanded Tregs + EP11313 was detected. Interestingly, this group exhibited a significant diminution of GVHD clinical score with less skin and ocular involvement. Finally, using low numbers of highly purified expanded Tregs, improved clinical GVHD scores were observed in EP11313 treated recipients. In total, we conclude that use of this novel combinatorial strategy can suppress pre-clinical GVHD and posit, EP11313 treatment might be useful combined with Treg expansion therapy for treatment of diseases involving inflammatory responses.

Approximately 5% of individuals chronically infected with develop pulmonary hypertension (PH). The disease is progressive and often fatal, and treatment options are palliative, not curative. Recent studies have unraveled major players of the Th2 inflammation axis in the -induced PH pathology using murine models and studying human samples. TGF-β signaling is a link between the Type 2 inflammation and vascular remodeling, and specifically Thrombospondin-1 (TSP-1) is upregulated by the inflammation and activates TGF-β. Overall, the current model for the pathogenesis of -induced PH is that deposition of eggs in the pulmonary vasculature results in localized Th2 inflammation, leading to TGF-β activation by TSP-1, and the active TGF-β then results in vascular remodeling and PH.

BACKGROUND

Medical cannabis laws (MCL) have received increased attention as potential drivers of cannabis use (CU), but little work has explored how the broader policy climate, independent of MCL, may impact CU outcomes. We explored the association between state-level policy liberalism and past-year cannabis use (CU) and cannabis use disorder (CUD).

METHODS

We obtained state-level prevalence of past-year CU and CUD among past year cannabis users for ages 12-17, 18-25, and 26+ from the 2004-2006 and 2010-2012 National Surveys on Drug Use and Health. States were categorized as liberal, moderate, or conservative based on state-level policy liberalism rankings in 2005 and 2011. Linear models with random state effects examined the association between policy liberalism and past-year CU and CUD, adjusting for state-level social and economic covariates and medical cannabis laws.

RESULTS

In adjusted models, liberal states had higher average past-year CU than conservative states for ages 12-17 (+1.58 percentage points; p = 0.03) and 18-25 (+2.96 percentage points; p = 0.01) but not for 26+ (p = 0.19). CUD prevalence among past year users was significantly lower in liberal compared to conservative states for ages 12-17 (-2.87 percentage points; p = 0.045) and marginally lower for ages 26+ (-2.45 percentage points; p = 0.05).

CONCLUSION

Liberal states had higher past-year CU, but lower CUD prevalence among users, compared to conservative states. Researchers and policy makers should consider how the broader policy environment, independent of MCL, may contribute to CU outcomes.