Is chronic AhR activation by rapidly metabolized ligands safe for the treatment of immune-mediated diseases?

Abstract

There is a long standing perception that AhR ligands are automatically disqualified from pharmaceutical development due to their induction of Cyp1a1 as well as their potential for causing “dioxin-like” toxicities. However, recent discoveries of new AhR ligands with potential therapeutic applications have been reported, inviting reconsideration of this policy. One area of exploration is focused on the activation of AhR to promote the generation of regulatory T cells, which control the intensity and duration of immune responses. Rapidly metabolized AhR ligands (RMAhRLs), which do not bioaccumulate in the same manner as 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) have been discovered that induce Tregs and display impressive therapeutic efficacy in a broad range of preclinical models of immune-mediated diseases. Given the promise of these RMAhRLs, is the bias against AhR activators still valid? Can RMAhRLs be given chronically to maintain therapeutic levels of AhR activation without producing the same toxicity profile as dioxin-like compounds? Based on our review of the data, there is little evidence to support the indiscriminate exclusion of AhR activators/Cyp1a1 inducers from early drug developmental pipelines. We also found no evidence that short-term treatment with RMAhRLs produce “dioxin-like toxicity” and, in fact, were well tolerated. However, safety testing of individual RMAhRLs under therapeutic conditions, as performed with all promising new drugs, will be needed to reveal whether or not chronic activation of AhR leads to unacceptable adverse outcomes.

The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health

“…Because a key event in AhR-mediated signaling is prolonged AhR degradation following ligand binding [155,156], it is possible that AhR-mediated pathogenicity versus protection in response to TCDD versus CS, respectively, is a consequence of the chronicity of AhR activation- and therefore degradation. This possibility is further strengthened by observations that although TCDD, FICZ and ITE are all high affinity AhR agonists [2], FICZ and ITE are rapidly metabolized and likely non-toxic [157], whereas TCDD is persistent and regarded as highly toxic. Another potential explanation is that there are additional ligand-dependent differences can mediate both pathogenic and protective effects of the AhR in a cell- or context-specific manner.…”

Aryl Hydrocarbon Receptor (AHR) Ligands as Selective AHR Modulators (SAhRMs)

“…The number of individual compounds that bind to and modulate AhR-mediated responses and genes is continually increasing, and includes structurally diverse synthetic chemicals (e.g., pharmaceuticals), phytochemicals, microbial metabolites and endogenous biochemicals, some of which may be “cognate” AhR ligands [ 4 , 5 , 6 , 94 , 96 , 103 , 104 , 105 , 106 , 107 ]. Most but not all of these compounds bind the receptor, with much lower binding affinities than observed for TCDD.…”

“…Most but not all of these compounds bind the receptor, with much lower binding affinities than observed for TCDD. Some of these AhR ligands fit into the category of rapidly metabolized AhR ligands (RMAhRLs) [ 106 , 107 ]. This part of the review will examine and provide some examples of how different classes of AhR ligands are highly selective in terms of their agonist and antagonist activities, suggesting that they are SAhRMs.…”

AhR activation increases IL‐2 production by alloreactive CD4+ T cells initiating the differentiation of mucosal‐homing Tim3+Lag3+ Tr1 cells

“…Accordingly, treatment of mice with AhR ligands has been shown to ameliorate the development of several T‐cell dependent autoimmune diseases, such as type 1 diabetes , inflammatory bowel disease , and experimental autoimmune encephalomyelitis , as well as to suppress transplant rejection and inhibit graft‐versus‐host (GVH) disease . The potent efficacy of AhR ligands in these preclinical models supports the development of AhR ligands for therapeutic use in prevention and treatment of immune‐mediated diseases . However, the clinical development of AhR ligands will be facilitated by a better understanding of the mechanisms by which AhR signaling induces such profound immunosuppressive effects.…”