RESUMEN
Aspergillus fumigatus is an opportunistic fungal pathogen of immunocompromised patient populations. Mortality is thought to be context-specific and occurs via both enhanced fungal growth and immunopathogenesis. NLRX1 is a negative regulator of immune signaling and metabolic pathways implicated in host responses to microbes, cancers, and autoimmune diseases. Our study indicates loss of Nlrx1 results in enhanced fungal burden, pulmonary inflammation, immune cell recruitment, and mortality across immuno-suppressed and immuno-competent models of IPA using two clinically derived isolates (AF293, CEA10). We observed that the heightened mortality is due to enhanced recruitment of CD103+ dendritic cells (DCs) that produce elevated amounts of IL-4 resulting in a detrimental Th2-mediated immune response. Adoptive transfer of Nlrx1-/- CD103+ DCs in neutropenic NRG mice results in enhanced mortality that can be ablated using IL-4 neutralizing antibodies. In vitro analysis of CD103+ DCs indicates loss of Nlrx1 results in enhanced IL-4 production via elevated activation of the JNK/JunB pathways. Interestingly, loss of Nlrx1 also results in enhanced recruitment of monocytes and neutrophils. Chimeras of irradiated Nlrx1-/- mice reconstituted with wild type bone marrow have enhanced neutrophil recruitment and survival during models of IPA. This enhanced immune cell recruitment in the absence of Nlrx1 is mediated by excessive production of CXCL8/IL-8 family of chemokines and IL-6 via early and enhanced activation of P38 in response to A. fumigatus conidia as shown in BEAS-2B airway epithelial cells. In summary, our results point strongly towards the cell-specific and contextual function of Nlrx1 during invasive pulmonary aspergillosis and may lead to novel therapeutics to reduce Th2 responses by CD103+ DCs or heightened recruitment of neutrophils.
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Aspergillus fumigatus/inmunología , Células Dendríticas/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Proteínas Mitocondriales/inmunología , Aspergilosis Pulmonar/inmunología , Células Th2/inmunología , Animales , Línea Celular , Citocinas/genética , Citocinas/inmunología , MAP Quinasa Quinasa 4/genética , MAP Quinasa Quinasa 4/inmunología , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Noqueados , Proteínas Mitocondriales/genética , Neutrófilos/inmunología , Neutrófilos/patología , Aspergilosis Pulmonar/genética , Aspergilosis Pulmonar/patología , Células Th2/patología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Proteínas Quinasas p38 Activadas por Mitógenos/inmunologíaRESUMEN
Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is an emerging therapeutic target for a spectrum of human diseases. NX-13 is a small molecule therapeutic designed to target and activate NLRX1 to induce immunometabolic changes resulting in lower inflammation and therapeutic responses in inflammatory bowel disease (IBD). This study investigates the safety of NX-13 in a seven-day, repeat-dose general toxicity study in male and female Sprague Dawley rats at oral doses of 500 and 1000 mg/kg. Weights, clinical signs, functional observational battery, clinical pathology and histopathology were used for evaluation. Daily oral dosing of NX-13 up to 1000 mg/kg did not result in any changes in weight, abnormal clinical signs or behavior. No significant differences were observed between treated and control rats in hematology or blood biochemistry. Histopathological evaluation of 12 tissues demonstrated no differences between controls and treated rats. There were no changes in weights of brain, heart, kidney, liver or spleen. Pharmacokinetic analysis of a single oral dose of NX-13 at 10 mg/kg in Sprague Dawley rats provided a maximum plasma concentration of 57 ng/mL at 0.5 h post-dose. Analysis of colon tissue after oral dosing with 1 and 10 mg/kg indicated high peak concentrations (10 and 100 µg/g, respectively) that scale in a dose-proportional manner. These experiments suggest that NX-13 is safe and well-tolerated in rats given oral doses as high as 1000 mg/kg with a favorable gastrointestinal localized pharmacokinetic profile, confirming NX-13 as a promising therapeutic for Crohn's disease and ulcerative colitis.
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Enfermedades Inflamatorias del Intestino , Roedores , Administración Oral , Animales , Femenino , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Masculino , Piridinas , Ratas , Ratas Sprague-DawleyRESUMEN
Inflammatory bowel disease (IBD) is an expanding autoimmune disease afflicting millions that remains difficult to treat due to the accumulation of multiple immunological changes. BT-11 is an investigational new drug for IBD that is orally active, gut restricted, and targets the lanthionine synthetase C-like 2 immunometabolic pathway. CD25+ FOXP3+ CD4+ T cells are increased locally within the colon of BT-11-treated mice in Citrobacter rodentium and IL-10-/- mouse models of colitis. The maintained efficacy of BT-11 in the absence of IL-10 combined with the loss of efficacy when direct cell-cell interactions are prevented suggest that the regulatory T cell (Treg)-related elements of suppression are cell contact-mediated. When PD-1 is inhibited, both in vitro and in vivo, the efficacy of BT-11 is reduced, validating this assertion. The depletion of CD25+ cells in vivo abrogated the retention of therapeutic efficacy postdiscontinuation of treatment, indicating that Tregs are implicated in the maintenance of tolerance mediated by BT-11. Furthermore, the involvement of CD25 suggested a role of BT-11 in IL-2 signaling. Cotreatment with BT-11 and IL-2 greatly enhances the differentiation of CD25+ FOXP3+ cells from naive CD4+ T cells relative to either alone. BT-11 enhances phosphorylation of STAT5, providing a direct linkage to the regulation of FOXP3 transcription. Notably, when STAT5 is inhibited, the effects of BT-11 on the differentiation of Tregs are blocked. BT-11 effectively enhances the IL-2/STAT5 signaling axis to induce the differentiation and stability of CD25+ FOXP3+ cells in the gastrointestinal mucosa to support immunoregulation and immunological tolerance in IBD.
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Bencimidazoles/farmacología , Mucosa Gástrica/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/inmunología , Piperazinas/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Colitis/inmunología , Mucosa Gástrica/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Inflammatory bowel disease (IBD) is a complex autoimmune disease with dysfunction in pattern-recognition responses, including within the NLR family. Nucleotide-binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) is a unique NLR with regulatory and anti-inflammatory functions resulting in protection from IBD in mouse models. NX-13 is an orally active, gut-restricted novel drug candidate that selectively targets and activates the NLRX1 pathway locally in the gut. In vitro and in vivo efficacy of NLRX1 activation by NX-13 was examined. Oral treatment with NX-13 alleviates disease severity, colonic leukocytic infiltration, and cytokine markers of inflammation in three mouse models of IBD (dextran sulfate sodium, Mdr1a-/-, and CD45RBhi adoptive transfer). Treatment of naive CD4+ T cells with NX-13 in vitro decreases differentiation into Th1 and Th17 subsets with increased oxidative phosphorylation and decreased NF-κB activation and reactive oxygen species. With stimulation by PMA/ionomycin, TNF-α, or H2O2, PBMCs from ulcerative colitis patients treated with NX-13 had decreased NF-κB activity, TNF-α+ and IFN-γ+ CD4+ T cells and overall production of IL-6, MCP1, and IL-8. NX-13 activates NLRX1 to mediate a resistance to both inflammatory signaling and oxidative stress in mouse models and human primary cells from ulcerative colitis patients with effects on NF-κB activity and oxidative phosphorylation. NX-13 is a promising oral, gut-restricted NLRX1 agonist for treating IBD.
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Derivados del Benceno/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Proteínas Mitocondriales/metabolismo , Piridinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Derivados del Benceno/administración & dosificación , Derivados del Benceno/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Mitocondriales/agonistas , Fosforilación Oxidativa/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVES: Misophonia is a highly prevalent yet understudied condition characterized by aversion toward particular environmental sounds. Oral/nasal sounds (e.g., chewing, breathing) have been the focus of research, but variable experiences warrant an objective investigation. Experiment 1 asked whether human-produced oral/nasal sounds were more aversive than human-produced nonoral/nasal sounds and non-human/nature sounds. Experiment 2 additionally asked whether machine-learning algorithms could predict the presence and severity of misophonia. METHOD: Sounds were presented to individuals with misophonia (Exp.1: N = 48, Exp.2: N = 45) and members of the general population (Exp.1: N = 39, Exp.2: N = 61). Aversiveness ratings to each sound were self-reported. RESULTS: Sounds from all three source categories-not just oral/nasal sounds-were rated as significantly more aversive to individuals with misophonia than controls. Further, modeling all sources classified misophonia with 89% accuracy and significantly predicted misophonia severity (r = 0.75). CONCLUSIONS: Misophonia should be conceptualized as more than an aversion to oral/nasal sounds, which has implications for future diagnostics and experimental consistency moving forward.
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Hiperacusia , Masticación , Humanos , Autoinforme , SonidoRESUMEN
Helicobacter pylori, the dominant member of the human gastric microbiota, elicits immunoregulatory responses implicated in protective versus pathological outcomes. To evaluate the role of macrophages during infection, we employed a system with a shifted proinflammatory macrophage phenotype by deleting PPARγ in myeloid cells and found a 5- to 10-fold decrease in gastric bacterial loads. Higher levels of colonization in wild-type mice were associated with increased presence of mononuclear phagocytes and in particular with the accumulation of CD11b+F4/80hiCD64+CX3CR1+ macrophages in the gastric lamina propria. Depletion of phagocytic cells by clodronate liposomes in wild-type mice resulted in a reduction of gastric H. pylori colonization compared with nontreated mice. PPARγ-deficient and macrophage-depleted mice presented decreased IL-10-mediated myeloid and T cell regulatory responses soon after infection. IL-10 neutralization during H. pylori infection led to increased IL-17-mediated responses and increased neutrophil accumulation at the gastric mucosa. In conclusion, we report the induction of IL-10-driven regulatory responses mediated by CD11b+F4/80hiCD64+CX3CR1+ mononuclear phagocytes that contribute to maintaining high levels of H. pylori loads in the stomach by modulating effector T cell responses at the gastric mucosa.
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Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/inmunología , Macrófagos/inmunología , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Helicobacter pylori , Ratones , Ratones Endogámicos C57BLRESUMEN
Nucleotide oligomerization domain-like receptor X1 (NLRX1) has been implicated in viral response, cancer progression, and inflammatory disorders; however, its role as a dual modulator of CD4+ T cell function and metabolism has not been defined. The loss of NLRX1 results in increased disease severity, populations of Th1 and Th17 cells, and inflammatory markers (IFN-γ, TNF-α, and IL-17) in mice with dextran sodium sulfate-induced colitis. To further characterize this phenotype, we used in vitro CD4+ T cell-differentiation assays and show that NLRX1-deficient T cells have a greater ability to differentiate into an inflammatory phenotype and possess greater proliferation rates. Further, NLRX1-/- cells have a decreased responsiveness to immune checkpoint pathways and greater rates of lactate dehydrogenase activity. When metabolic effects of the knockout are impaired, NLRX1-deficient cells do not display significant differences in differentiation or proliferation. To confirm the role of NLRX1 specifically in T cells, we used an adoptive-transfer model of colitis. Rag2-/- mice receiving NLRX1-/- naive or effector T cells experienced increased disease activity and effector T cell populations, whereas no differences were observed between groups receiving wild-type or NLRX1-/- regulatory T cells. Metabolic effects of NLRX1 deficiency are observed in a CD4-specific knockout of NLRX1 within a Citrobacter rodentium model of colitis. The aerobic glycolytic preference in NLRX1-/- effector T cells is combined with a decreased sensitivity to immunosuppressive checkpoint pathways to provide greater proliferative capabilities and an inflammatory phenotype bias leading to increased disease severity.
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Citrobacter rodentium/inmunología , Colitis/inmunología , Infecciones por Enterobacteriaceae/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Proteínas Mitocondriales/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Proliferación Celular/genética , Células Cultivadas , Colitis/inducido químicamente , Sulfato de Dextran , Modelos Animales de Enfermedad , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Mitocondriales/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies. Oral BT-11 did not cause any clinical signs of toxicity, biochemical or hematological changes, or macroscopic or microscopic changes to organs in 90-day repeat-dose toxicity studies in rats and dogs at doses up to 1,000 mg/kg/d. Oral BT-11 resulted in low systemic exposure in both rats (area under the curve exposure from t = 0 to t = 8 hours [AUC0-8] of 216 h × ng/mL) and dogs (650 h × ng/mL) and rapid clearance with an average half-life of 3 hours. BT-11 did not induce changes in respiratory function, electrocardiogram parameters, or behavior with single oral doses of 1,000 mg/kg/d. There was no evidence of mutagenic or genotoxic potential for BT-11 up to tested limit doses using an Ames test, chromosomal aberration assay in human peripheral blood lymphocytes, or micronucleus assay in rats. Therefore, nonclinical studies show BT-11 to be a safe and well-tolerated oral therapeutic with potential as a potent immunometabolic therapy for UC and CD with no-observed adverse effect level >1,000 mg/kg in in vivo studies.
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Bencimidazoles/farmacocinética , Bencimidazoles/toxicidad , Proteínas de la Membrana/antagonistas & inhibidores , Piperazinas/farmacocinética , Piperazinas/toxicidad , Administración Oral , Animales , Perros , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Ratas Wistar , Pruebas de ToxicidadRESUMEN
PURPOSE OF REVIEW: To highlight recent advances in the understanding of nutritional immunology and in the development of novel therapeutics for inflammatory bowel disease (IBD). RECENT FINDINGS: We highlight the variety of factors that contribute to the interaction of the immune system and nutrition including the microbiome and the nervous system stimulation of the gut. We describe the potential for therapeutic development in IBD. Further, we review the cellular metabolic effects on immune activation and promising therapeutic targets. Finally, we show how the progression of understanding the role of lanthionine synthetase C-like 2 has encompassed both nutritional and therapeutic advances and led to the development of novel oral small molecule therapeutics for IBD. SUMMARY: Nutritional immunology and drug development research centered around immunoregulatory pathways can provide safer and more effective drugs while accelerating the path to cures.
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Descubrimiento de Drogas/métodos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Fenómenos Fisiológicos de la Nutrición/inmunología , Fármacos Gastrointestinales/uso terapéutico , Microbioma Gastrointestinal , Humanos , Enfermedades Inflamatorias del Intestino/microbiología , Terapia Molecular Dirigida/métodos , Investigación Biomédica Traslacional/métodosRESUMEN
T follicular helper (Tfh) cells are a highly plastic subset of CD4+ T cells specialized in providing B cell help and promoting inflammatory and effector responses during infectious and immune-mediate diseases. Helicobacter pylori is the dominant member of the gastric microbiota and exerts both beneficial and harmful effects on the host. Chronic inflammation in the context of H. pylori has been linked to an upregulation in T helper (Th)1 and Th17 CD4+ T cell phenotypes, controlled in part by the cytokine, interleukin-21. This study investigates the differentiation and regulation of Tfh cells, major producers of IL-21, in the immune response to H. pylori challenge. To better understand the conditions influencing the promotion and inhibition of a chronically elevated Tfh population, we used top-down and bottom-up approaches to develop computational models of Tfh and T follicular regulatory (Tfr) cell differentiation. Stability analysis was used to characterize the presence of two bi-stable steady states in the calibrated Tfh/Tfr models. Stochastic simulation was used to illustrate the ability of the parameter set to dictate two distinct behavioral patterns. Furthermore, sensitivity analysis helped identify the importance of various parameters on the establishment of Tfh and Tfr cell populations. The core network model was expanded into a more comprehensive and predictive model by including cytokine production and signaling pathways. From the expanded network, the interaction between TGFB-Induced Factor Homeobox 1 (Tgif1) and the retinoid X receptor (RXR) was displayed to exert control over the determination of the Tfh response. Model simulations predict that Tgif1 and RXR respectively induce and curtail Tfh responses. This computational hypothesis was validated experimentally by assaying Tgif1, RXR and Tfh in stomachs of mice infected with H. pylori.
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Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular , Simulación por Computador , Proteínas de Homeodominio/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Ratones Endogámicos C57BL , Modelos Biológicos , Proteínas Represoras/metabolismo , Receptores X Retinoide/metabolismo , Procesos EstocásticosRESUMEN
People often choose suboptimal attentional control strategies during visual search. This has been at least partially attributed to the avoidance of the cognitive effort associated with the optimal strategy, but aspects of the task triggering such avoidance remain unclear. Here, we attempted to measure effort avoidance of an isolated task component to assess whether this component might drive suboptimal behavior. We adopted a modified version of the Adaptive Choice Visual Search (ACVS), a task designed to measure people's visual search strategies. To perform optimally, participants must make a numerosity judgment-estimating and comparing two color sets-before they can advantageously search through the less numerous of the two. If participants skip the numerosity judgment step, they can still perform accurately, albeit substantially more slowly. To study whether effort associated with performing the optional numerosity judgment could be an obstacle to optimal performance, we created a variant of the demand selection task to quantify the avoidance of numerosity judgment effort. Results revealed a robust avoidance of the numerosity judgment, offering a potential explanation for why individuals choose suboptimal strategies in the ACVS task. Nevertheless, we did not find a significant relationship between individual numerosity judgment avoidance and ACVS optimality, and we discussed potential reasons for this lack of an observed relationship. Altogether, our results showed that the effort avoidance for specific subcomponents of a visual search task can be probed and linked to overall strategy choices.
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When performing novel tasks, we often apply the rules we have learned from previous, similar tasks. Knowing when to generalize previous knowledge, however, is a complex challenge. In this study, we investigated the properties of learning generalization in a visual search task, focusing on the role of search difficulty. We used a spatial probability learning paradigm in which individuals learn to prioritize their search toward the locations where a target appears more often (i.e., high-probable location) than others (i.e., low-probable location) in a search display. In the first experiment, during a training phase, we intermixed the easy and difficult search trials within blocks, and each was respectively paired with a distinct high-probable location. Then, during a testing phase, we removed the probability manipulation and assessed any generalization of spatial biases to a novel, intermediate difficulty task. Results showed that, as training progressed, the easy search evoked a stronger spatial bias to its high-probable location than the difficult search. Moreover, there was greater generalization of the easy search learning than difficult search learning at test, revealed by a stronger bias toward the former's high-probable location. Two additional experiments ruled out alternatives that learning during difficult search itself is weak and learning during easy search specifically weakens learning of the difficult search. Overall, the results demonstrate that easy search interferes with difficult search learning and generalizability when the two levels of search difficulty are intermixed.
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Misophonia, a heightened aversion to certain sounds, turns common cognitive and social exercises (e.g., paying attention during a lecture near a pen-clicking classmate, coexisting at the dinner table with a food-chomping relative) into challenging endeavors. How does exposure to triggering sounds impact cognitive and social judgments? We investigated this question in a sample of 65 participants (26 misophonia, 39 control) from the general population. In Phase 1, participants saw faces paired with auditory stimuli while completing a gender judgment task, then reported sound discomfort and identification. In Phase 2, participants saw these same faces with novel ones and reported face likeability and memory. For both oral and non-oral triggers, misophonic participants gave higher discomfort ratings than controls did-especially when identification was correct-and performed slower on the gender judgment. Misophonic participants rated lower likeability than controls did for faces they remembered with high discomfort sounds, and face memory was worse overall for faces originally paired with high discomfort sounds. Altogether, these results suggest that misophonic individuals show impairments on social and cognitive judgments if they must endure discomforting sounds. This experiment helps us better understand the day-to-day impact of misophonia and encourages usage of individualized triggers in future studies.
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Cognición , Juicio , Humanos , Masculino , Femenino , Cognición/fisiología , Adulto , Adulto Joven , Estimulación Acústica , Memoria/fisiologíaRESUMEN
People tend to employ suboptimal attention control strategies during visual search. Here we question why people are suboptimal, specifically investigating how knowledge of the optimal strategies and the time available to apply such strategies affect strategy use. We used the Adaptive Choice Visual Search (ACVS), a task designed to assess attentional control optimality. We used explicit strategy instructions to manipulate explicit strategy knowledge, and we used display previews to manipulate time to apply the strategies. In the first two experiments, the strategy instructions increased optimality. However, the preview manipulation did not significantly boost optimality for participants who did not receive strategy instruction. Finally, in Experiments 3A and 3B, we jointly manipulated preview and instruction with a larger sample size. Preview and instruction both produced significant main effects; furthermore, they interacted significantly, such that the beneficial effect of instructions emerged with greater preview time. Taken together, these results have important implications for understanding the strategic use of attentional control. Individuals with explicit knowledge of the optimal strategy are more likely to exploit relevant information in their visual environment, but only to the extent that they have the time to do so.
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Atención , Reconocimiento Visual de Modelos , Tiempo de Reacción , Humanos , Reconocimiento Visual de Modelos/fisiología , Orientación , Conducta de Elección , Adulto Joven , Femenino , MasculinoRESUMEN
Lanthionine synthetase C-like 2 (LANCL2) therapeutics have gained increasing recognition as a novel treatment modality for a wide range of autoimmune diseases. Genetic ablation of LANCL2 in mice results in severe inflammatory phenotypes in inflammatory bowel disease (IBD) and lupus. Pharmacological activation of LANCL2 provides therapeutic efficacy in mouse models of intestinal inflammation, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. Mechanistically, LANCL2 activation enhances regulatory CD4â +â T cell (Treg) responses and downregulates effector responses in the gut. The stability and suppressive capacities of Treg cells are enhanced by LANCL2 activation through engagement of immunoregulatory mechanisms that favor mitochondrial metabolism and amplify IL-2/CD25 signaling. Omilancor, the most advanced LANCL2 immunoregulatory therapeutic in late-stage clinical development, is a phase 3 ready, first-in-class, gut-restricted, oral, once-daily, small-molecule therapeutic in clinical development for the treatment of UC and CD. In this review, we discuss this novel mechanism of mucosal immunoregulation and how LANCL2-targeting therapeutics could help address the unmet clinical needs of patients with autoimmune diseases, starting with IBD.
Oral LANCL2 therapeutics are a safe and effective treatment modality for the long-term management of autoimmune diseases, including UC and CD, without causing systemic immunosuppression. This review discusses in detail the immunoregulatory mechanisms of action of LANCL2 therapeutics. More specifically, the article describes how omilancor, a first-in-class, oral, once daily, gut-restricted LANCL2 therapeutic could help address the unmet clinical needs of patients with IBD and other immune-mediated diseases.
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Enfermedades Autoinmunes , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Animales , Ratones , Colitis Ulcerosa/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Linfocitos T Reguladores/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión a FosfatoRESUMEN
We are often bombarded with salient stimuli that capture our attention and distract us from our current goals. Decades of research have shown the robust detrimental impacts of salient distractors on search performance and, of late, in leading to altered feature perception. These feature errors can be quite extreme, and thus, undesirable. In search tasks, salient distractors can be suppressed if they appear more frequently in one location, and this learned spatial suppression can lead to reductions in the cost of distraction as measured by reaction time slowing. Can learned spatial suppression also protect against visual feature errors? To investigate this question, participants were cued to report one of four briefly presented colored squares on a color wheel. On two-thirds of trials, a salient distractor appeared around one of the nontarget squares, appearing more frequently in one location over the course of the experiment. Participants' responses were fit to a model estimating performance parameters and compared across conditions. Our results showed that general performance (guessing and precision) improved when the salient distractor appeared in a likely location relative to elsewhere. Critically, feature swap errors (probability of misreporting the color at the salient distractor's location) were also significantly reduced when the distractor appeared in a likely location, suggesting that learned spatial suppression of a salient distractor helps protect the processing of target features. This study provides evidence that, in addition to helping us avoid salient distractors, suppression likely plays a larger role in helping to prevent distracting information from being encoded.
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Atención , Aprendizaje , Humanos , Tiempo de Reacción/fisiología , Atención/fisiología , Señales (Psicología) , ProbabilidadRESUMEN
BACKGROUND: Clostridioides difficile infection (CDI) is an opportunistic infection of the gastrointestinal tract, commonly associated with antibiotic administration, that afflicts almost 500 000 people yearly only in the United States. CDI incidence and recurrence is increased in inflammatory bowel disease (IBD) patients. Omilancor is an oral, once daily, first-in-class, gut-restricted, immunoregulatory therapeutic in clinical development for the treatment of IBD. METHODS: Acute and recurrent murine models of CDI and the dextran sulfate sodium-induced concomitant model of IBD and CDI were utilized to determine the therapeutic efficacy of oral omilancor. To evaluate the protective effects against C. difficile toxins, in vitro studies with T84 cells were also conducted. 16S sequencing was employed to characterize microbiome composition. RESULTS: Activation of the LANCL2 pathway by oral omilancor and its downstream host immunoregulatory changes decreased disease severity and inflammation in the acute and recurrence models of CDI and the concomitant model of IBD/CDI. Immunologically, omilancor treatment increased mucosal regulatory T cell and decreased pathogenic T helper 17 cell responses. These immunological changes resulted in increased abundance and diversity of tolerogenic gut commensal bacterial strains in omilancor-treated mice. Oral omilancor also resulted in accelerated C. difficile clearance in an antimicrobial-free manner. Furthermore, omilancor provided protection from toxin damage, while preventing the metabolic burst observed in intoxicated epithelial cells. CONCLUSIONS: These data support the development of omilancor as a novel host-targeted, antimicrobial-free immunoregulatory therapeutic for the treatment of IBD patients with C. difficile-associated disease and pathology with the potential to address the unmet clinical needs of ulcerative colitis and Crohn's disease patients with concomitant CDI.
Omilancor is an oral, gut-restricted first-in-class immunoregulatory therapeutic for the treatment of inflammatory bowel disease (IBD). This study demonstrates for the first time that omilancor provides therapeutic efficacy in models of acute and recurrent Clostridioides difficile infection (CDI), and concomitant CDI and IBD, by increasing regulatory T cell function while suppressing effector responses, plus modulating gut microbiome composition and preserving epithelial barrier function.
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Clostridioides difficile , Infecciones por Clostridium , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Animales , Ratones , Enfermedades Inflamatorias del Intestino/complicaciones , Antibacterianos/uso terapéutico , Infecciones por Clostridium/microbiología , Enfermedad de Crohn/tratamiento farmacológico , Proteínas de la Membrana , Proteínas de Unión a FosfatoRESUMEN
Hypothesis-driven research rests on clearly articulated scientific theories. The building blocks for communicating these theories are scientific terms. Obviously, communication - and thus, scientific progress - is hampered if the meaning of these terms varies idiosyncratically across (sub)fields and even across individual researchers within the same subfield. We have formed an international group of experts representing various theoretical stances with the goal to homogenize the use of the terms that are most relevant to fundamental research on visual distraction in visual search. Our discussions revealed striking heterogeneity and we had to invest much time and effort to increase our mutual understanding of each other's use of central terms, which turned out to be strongly related to our respective theoretical positions. We present the outcomes of these discussions in a glossary and provide some context in several essays. Specifically, we explicate how central terms are used in the distraction literature and consensually sharpen their definitions in order to enable communication across theoretical standpoints. Where applicable, we also explain how the respective constructs can be measured. We believe that this novel type of adversarial collaboration can serve as a model for other fields of psychological research that strive to build a solid groundwork for theorizing and communicating by establishing a common language. For the field of visual distraction, the present paper should facilitate communication across theoretical standpoints and may serve as an introduction and reference text for newcomers.
RESUMEN
The mental experience of attention capture has attracted a great deal of intrigue among researchers seeking to explain the interactions between stimulus-driven and goal-driven attentional control. In recent years, researchers have increasingly begun to analyze cumulative response time (RT) distributions to test modern accounts of the capture phenomenon, particularly accounts claiming that there are changes in susceptibility to distraction as a function of time. In this paper, we raise a criticism of this approach, which centers on a problematic assumption. The assumption is that variability in these distributions is primarily determined by fluctuations in the observer's internal control state (e.g., readiness for the trial). However, it is also the case that faster segments of the distributions are overrepresented by trials that are objectively easy, while slower segments are overrepresented by trials that are objectively difficult. That is, incidental aspects of the trial stimuli influence task performance independently of the observer's internal control state. Here, we demonstrate empirically that contributions of incidental stimulus factors distort cumulative RT distributions in such a way that confounds proper interpretation of experimental data. The results have implications for theoretical accounts of attentional control, and they also raise caution about the assumptions that are sometimes made when analyzing cumulative RT distributions.
Asunto(s)
Atención , Tiempo de Reacción/fisiología , Percepción Visual/fisiología , Humanos , Distorsión de la Percepción/fisiología , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Learning to ignore distractors is critical for navigating the visual world. Research has suggested that a location frequently containing a salient distractor can be suppressed. How does such suppression work? Previous studies provided evidence for proactive suppression, but methodological limitations preclude firm conclusions. We sought to overcome these limitations with a new search-probe paradigm. On search trials, participants searched for a shape oddball target while a salient color singleton distractor frequently appeared in a high-probability location. On randomly interleaved probe trials, participants discriminated the orientation of a tilted bar presented briefly at one of the search locations, allowing us to index the spatial distribution of attention at the moment the search would have begun. Results on search trials replicated previous findings: reduced attentional capture when a salient distractor appeared in the high-probability location. However, critically, probe discrimination was no different at the high-probability and low-probability locations. We increased the incentive to ignore the high-probability location in Experiment 2 and found, strikingly, that probe discrimination accuracy was greater at the high-probability location. These results suggest that the high-probability location was initially selected before being suppressed, consistent with a reactive mechanism. Overall, the accuracy probe procedure demonstrates that learned spatial suppression is not always proactive, even when response time metrics seem consistent with such an inference. (PsycInfo Database Record (c) 2023 APA, all rights reserved).