An emerging clinical issue associated with immune-oncology agents is the collateral effects on the tolerability of concomitant medications. One report of this phenomenon was the increased incidence of hypersensitivity reactions observed in patients receiving concurrent immune checkpoint inhibitors and sulfasalazine. Thus, the aim of this study was to characterize the T-cells involved in the pathogenesis of such reactions, and recapitulate the effects of inhibitory checkpoint blockade on de-novo priming responses to compounds within in-vitro platforms. A regulatory competent human dendritic cell/T-cell co-culture assay was used to model the effects of immune checkpoint inhibitors on de-novo nitroso sulfamethoxazole- and sulfapyridine (the sulfonamide component of sulfasalazine) hydroxylamine-specific priming responses. The role of T-cells in the pathogenesis of the observed reactions was explored in three patients through phenotypic characterization of sulfapyridine/sulfapyridine hydroxylamine-responsive T-cell clones, and assessment of cross-reactivity and pathways of T-cell activation. Augmentation of the frequency of responding drug-specific T-cells and intensity of the T-cell response was observed with PD-1/PD-L1 blockade. Monoclonal populations of sulfapyridine- and sulfapyridine hydroxylamine-responsive T-cells were isolated from all three patients. A core secretory effector molecule profile (IFN-γ, IL-13, granzyme B and perforin) was identified for sulfapyridine and sulfapyridine hydroxylamine responsive T-cell clones, which proceeded through Pi and hapten mechanisms, respectively. Data presented herein provides evidence that drug-responsive T-cells are effectors of hypersensitivity reactions observed in oncology patients administered immune checkpoint inhibitors and sulfasalazine. Perturbation of drug-specific T-cell priming is a plausible explanation for clinical observations of how an increased incidence of these adverse events is occurring.
Studies indicate that while suppressing smoking thoughts increases subsequent smoking, it may have no impact on desire to smoke. However, previous research has examined suppression of general smoking thoughts rather than thoughts specifically related to desire to smoke. The present study investigated whether suppression of thoughts of desire to smoke results in subsequently elevated ratings of desire to smoke. An experimental study examined the effects of suppressing thoughts of desire to smoke, versus expressing thoughts of desire to smoke, versus a control group thinking about anything, on ratings of desire to smoke and tobacco withdrawal symptoms at four time points (before manipulations, just after manipulations, 5 min after, 10 min after). In addition, effects of suppressing thoughts of desire to smoke on subsequent reports of thoughts of desire to smoke were examined. Suppressing the thoughts of desire to smoke caused thought rebound (i.e., greater subsequent reports of thoughts of desire to smoke). However, compared with control groups, this suppression did not elevate subsequent ratings of desire to smoke. Suppressing the thoughts of desire to smoke does not elevate subsequent ratings of this desire. Increased cigarette consumption following suppression of smoking thoughts may be mediated by mechanisms other than increased desire to smoke.
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