![]() In both IFN-γ knockout mice and mice treated with an IFN-γ-neutralizing antibody prior to opioid treatment, neural connections remained strong and unchanged throughout withdrawal even though the fragile-like Treg cells still infiltrated the brain. With the mechanism pieced together, the researchers also showed that they could break it down, at least in mice. ![]() boosts the entry of fragile-like Tregs into the and thereby contributes to structural and behavioral changes.” In short, as the paper puts it, “Opioid stimulation. Staining revealed that levels of other cytokines and inflammatory agents were unchanged, which the researchers took to mean that the fragile-like Treg cells (and specifically the IFN-γ they expressed) were driving changes in the nucleus accumbens-weakening synaptic connections among neurons-that then resulted in withdrawal symptoms in the mice. “I think the paper is really advancing the whole neuroimmune field and maybe our understanding of what immune mediators and cells are doing in the brain,” Eisenstein says. ![]() That stood out as particularly interesting to Eisenstein, she says: Chemokines are responsible for trafficking immune cell subsets that express the receptor for the respective chemokine, but the fact that the chemokine expression was coming from within the brain hints that brain cells have a larger role in the immune response than previously assumed. The study linked the vulnerability to openings in the blood-brain barrier caused by C-C motif chemokine ligand 2 (Ccl2) expression by nucleus accumbens neurons, which itself was facilitated by opioid exposure, and which increases Treg trafficking into the brain. Analysis of samples taken from the heroin-treated mice revealed that IFN-γ was not only more prevalent in the bloodstream, but also in the nucleus accumbens, a brain region that modulates goal-directed behaviors and reward pathways, making it relevant to understanding and treating addiction.Īccording to the study authors, the elevated IFN-γ in that region indicates that the fragile-like Treg cells were able to cross the blood-brain barrier, the protective layer that physically protects the brain from pathogens (and many pharmaceuticals) traveling through the body’s vasculature. Moving over to a mouse model, the researchers found that treating mice with heroin resulted in higher fragile-like Treg counts and, therefore, higher IFN-γ expression in the bloodstream. The study authors write that opioid-induced hypoxia may have caused the cells’ unexpected state, as hypoxia has been implicated in triggering fragile-like states in the Tregs near tumors. Tregs are usually involved in immunosuppression, but ones in this fragile-like state-which had previously only been observed in tumor microenvironments-lose their suppressive functions and instead produce the inflammatory cytokine interferon-γ (IFN-γ). Investigating further with a series of flow cytometry experiments, they found that the heroin-using group’s blood contained high levels of an unusual immune cell called fragile-like regulatory T cells (Tregs). In the study, the researchers examined the blood of 21 human heroin users and compared it to that of 20 controls, finding that the former group’s blood contained various biomarkers suggesting their immune systems were in disarray (As of this article’s publication, neither of the paper’s corresponding authors have responded to The Scientist’s request for an interview). “I think the paper is really a huge step forward.” Eisenstein says she was intrigued by the paper, which links withdrawal symptoms to an inflammatory immune response, because, as she wrote in a 2019 review article on the immune effects of morphine, decades of research have shown opioids and the immune cells implicated in the new study to be immunosuppressive, instead. “The work represents a major advance in the emerging field of neural-immune interactions and the role of immune cells and mediators in modulating neural processes during opioid exposure,” Temple University immunologist and substance abuse researcher Toby Eisenstein, who also didn’t work on the study, tells The Scientist. While some of the findings still need to be replicated and verified, Montaner says that the study presents scientists with “a roadmap for new clinical interventions to be tested” to prevent withdrawal and help people recovering from opioid addiction or dependence safely wean off of the drug and avoid reuse. Although the immune system has long been implicated in opioid withdrawal, the new findings, published January 19 in Cell, are the first to link the immune system’s interactions with the central nervous system and especially the blood-brain barrier to withdrawal, explains immunopathogenesis researcher Luis Montaner, who is a professor at the Wistar Institute in Philadelphia and didn’t work on the study.
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