Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy.

BACKGROUND: Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions. OBJECTIVE: This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT). METHODS: We first performed ex vivo T-cell profiling on peanut-reactive CD154+CD137+ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4+ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT. RESULTS: Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6-CRTH2+ and CCR6+CRTH2-). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of TH2A pTeff cells. PnOIT induced elimination of TH2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of TH2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation. CONCLUSION: Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.

Oral desensitization therapy for peanut allergy induces dynamic changes in peanut-specific immune responses.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.

Protean Kinematics: A Blended Model of VR Physics.

Avatar research largely focuses on the effects of the appearance and external characteristics of avatars, but may also warrant further consideration of the effects of avatar movement characteristics. With Protean kinematics, we offer an expansion the avatar-user appearances-based effects of the Proteus Effect to a systematic exploration into the role of movement in affecting social perceptions (about others) and idealized perceptions (about self). This work presents both a theoretical (typology) and methodological (physics-based measurement) approach to understanding the complex blend of physical inputs and virtual outputs that occur in the perceptual experience of VR, particularly in consideration of the collection of hippocampal (e.g., place cells, grid cells) and entorhinal neurons (e.g., speed cells) that fire topologically relative to physical movement in physical space. Offered is a novel method that distills the blend of physical and virtual kinematics to contribute to modern understandings of human-agent interaction and cognitive psychology.

User-Agent Bond in Generalizable Environments: Long-Term Risk-Reduction via Nudged Virtual Choices.

Avatars or agents are digitized self-representations of a player in mediated environments. While using agents to navigate through mediated environments, players form bonds with their self-agents or characters, a process referred to as identification. Identification can involve automatic, but temporary, self-concept "shifts in implicit self-perceptions" (Klimmt et al., 2010, p. 323) of the media user by adopting or emphasizing the action choices on behalf of the social expectation of the avatar in the mediated environment. In the current study, we test the possibility that users' identification with video game avatars-a bond built between avatars and players- would account for subsequent behavior changes. We did so by using 3-month longitudinal data involving a narratively-based serious game: Socially Optimized Learning in Virtual Environments (SOLVE), a 3D-interactive game designed to reduce risky sexual behaviors among young men who have sex with men (n = 444). Results show that video game identification predicts both the reduction of risky sexual behaviors over time, and reduction in the number of non-primary partners with whom risky sex occurs. And when players identify with the game character, they tend to make healthier choices, which significantly mediates the link between video game identification and reduction of risky behaviors.

Optimal human pathogenic TH2 cell effector function requires local epithelial cytokine signaling.

BACKGROUND: IL-33 is an emerging key factor in development of allergic diseases. The IL-33 receptor (suppressor of tumorigenicity [ST2]) is a differentially expressed gene in pathogenic TH2 cells, but its role in T-cell effector function has not been elucidated. OBJECTIVE: We investigated the role of IL-33 in modulating circulating allergen-specific T-cell responses. We hypothesized that selective ST2 expression on allergen-specific CD4+ T cells would confer susceptibility to the effects of IL-33. METHODS: PBMCs from subjects with food allergy, inhalant allergy, and no allergy were obtained on the basis of clinical history and serum IgE level. A T-cell receptor-dependent CD154 upregulation assay and direct peptide major histocompatibility complex class II tetramer staining were used to profile allergen-specific CD4+ T cells by flow cytometry. Allergen-specific CD4+ T cell cytokine production was evaluated during IL-33 exposure. ST2 expression was also tracked by using a 2-color flow-based assay. RESULTS: ST2 expression on peripheral allergen-specific CD4+ T cells was confined to subjects with allergy and restricted to TH2A cells. Comparison between direct peptide major histocompatibility complex class II tetramer staining and the CD154 functional assay identified ST2 as a marker of TH2A cell activation. IL-33 exposure enhanced IL-4 and IL-5 secretion in allergen-reactive TH2A cells. Allergen-induced ST2 expression on peripheral CD4+ T cells can be used to track allergen-reactive TH2A cells from donors with allergy. CONCLUSION: ST2 expression on circulating CD4+ T cells represents a transient phenotype associated with TH2A cell activation, allowing these cells to sense locally elicited tissue cytokines. IL-33 selectively amplifies pathogenic TH2 cell effector functions, suggesting a tissue checkpoint that may regulate adaptive allergic immunity.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Friends over Doctors? The Influences of Source and Perceived Customization on College Drinking.

College drinking, often associated with college binge drinking, is a critical issue in the United States and may lead to harmful consequences such as academic failure, injury, sexual assault, and even death. Health interventions targeted at reducing problematic drinking are needed to help prevent these harmful behaviors among college students. The current work explores the intersection of different types of information sources (e.g., authority and peer) and perceived customization on various health-related outcomes related to college drinking (e.g., trust, attitudes, and behavioral intentions). Undergraduate students (N = 448) were presented with health information regarding college drinking in a 2 (perceived customization or non-customization) × 3 (authority, peer, or technology source) between-subjects experimental design. We found a strong effect of peer source of health information, somewhat surprisingly more effective than information from a professional source (i.e., a medical physician). Moreover, the results underscore the importance of not only promoting perceived customization but also fostering a sense of agency with such interface features. Theoretical and practical implications for health-related outcomes are discussed.

An Experimental Investigation into Promoting Mental Health Service Use on Social Media: Effects of Source and Comments.

Mental health is an increasingly prevalent topic of public interest, but remains a complex area requiring focused research that must account for negative perceptions surrounding mental health issues. The current work explores the roles of social media information source credibility and valence of social media comments on health outcomes in such a mental health context. We used a 2 (message source: professional vs. layperson) × 3 (valence of comments: positive vs. negative vs. mixed) online experiment to examine the effects of source and valence of comments on trust, attitudes and intentions related to mental health information and services among 422 undergraduate students. Results supported the hypothesized model in which source influenced cognitive trust while comments influenced affective trust. Cognitive and affective trust both impacted attitudes towards mental health information which encourages the intention to share such information on social media. Additionally, affective trust impacted attitudes towards mental services which influenced intentions to seek them out. Source and valence of comments on social media impact different behavioral intentions regarding the use of mental health services. This study provides insights for future social media campaigns promoting mental health service use.

Associations of Social Media Use, Patient-centered Communication, and Knowledge with Perceived Human Papillomavirus Vaccine Effectiveness.

Objectives: Given the effectiveness of human papillomavirus (HPV) vaccination in preventing cervical cancer and other diseases, as well as the low rates of HPV vaccination in the United States, it is important to examine the determinants of perceived HPV vaccine effectiveness. In this study, we examined the associations between potential factors associated with perceived HPV vaccine effectiveness. Methods: We utilized data (N = 718) from the nationally representative 2017 Health Information National Trends Survey (HINTS). We examined the associations of health-related social media use, patient-centered communication, and HPV knowledge with perceived HPV vaccine effectiveness in preventing cervical cancer. We reported descriptive statistics, and conducted bivariable analyses, multivariable analysis, and mediation analyses. Results: Perceived HPV vaccine effectiveness was associated with sex, age, education, health-related social media use, and HPV knowledge. Additionally, HPV knowledge mediated the associations of health-related social media use and patient-centered communication with perceived HPV vaccine effectiveness. Conclusions: Improving health-related information from social media, patient-centered communication, and HPV knowledge may increase perceived HPV vaccine effectiveness and ultimately, vaccine adoption.

A Picture Worth a Thousand Texts? Investigating the Influences of Visual Appeals in a Text Message-Based Health Intervention.

Healthy eating among young people may curb obesity and improve health, but strong messaging is needed for healthy eating interventions. In the current work, we evaluated the usefulness of visual appeals in a pilot text message-based healthy eating intervention among college students. A 2 (gain vs. loss) × 2 (image vs. no image) design with pretest and posttest questionnaires (N = 111) revealed text-only messages with loss frames had an influence on affective risk response, while both gain- and loss-framed text messages with visual appeals had positive effects on attitudes and intentions. This pilot study provides evidence to support the feasibility of using visual appeals in text message-based health interventions. The implications of the current study are discussed.

An Experimental Investigation of Human Presence and Mobile Technologies on College Students' Sun Protection Intentions: Between-Subjects Study.

BACKGROUND: Health promotion and education programs are increasingly being adapted and developed for delivery through digital technologies. With this shift toward digital health approaches, it is important to identify design strategies in health education and promotion programs that enhance participant engagement and promote behavior change. OBJECTIVE: This study aimed to examine the impact of an experiment testing various mobile health (mHealth) skin cancer prevention messages on sun protection intentions and message perceptions among American college students. METHODS: A sample of 134 college students aged 18 years or older participated in a 2×2×2 between-subjects experimental study, designed to examine the individual and combinatory effects of multiple dimensions (human presence, screen size, and interactivity) of digital technologies. The primary study outcome was intention to use sun protection; secondary outcomes included attitudes toward the information, two dimensions of trust, and information processing. RESULTS: Generally, intention to use sun protection was positively associated with the presence of human characters in the health educational messages (P<.001), delivering educational health messages on a large screen (ie, iPad; P<.001), and higher interactivity (P<.001). Only human presence produced more favorable attitudes (P=.02). Affective trust was positively associated with human presence (P=.006) and large screen size (P<.001), whereas cognitive trust was positively associated with human presence (P<.001) and small screen size (P=.007). Moreover, large screen size led to more heuristic processing (P=.03), whereas small screen size led to more systematic processing (P=.04). CONCLUSIONS: This experimental study demonstrates that the impact of mHealth skin cancer prevention messages differs based on platform and delivery design features. Effects on behavioral intentions, attitudes, and trust were found for conditions with human presence, highlighting the importance of including this feature in mHealth programs. Results from this experimental study can be used to optimize the design of mHealth educational interventions that promote sun protection.

Virtual prognostication: When virtual alcohol choices predict change in alcohol consumption over 6-months.

Narrative games, in which users interact with virtual agents, are increasingly being used in health interventions to change targeted behaviors. In virtual social interactions, based on similar real-life contextual cues, past behavior can predict virtual choices. Here, based on theories in learning and interactivity, we examined the whether following a virtual intervention, choices in social interactions may be particularly diagnostic of future behavior changes. To test this, we needed to: (1) leverage a contextualized risk (e.g., involving alcohol consumption) scenario (e.g., having one more drink with my partner) given a target audience (e.g., sexually risky young men who have sex with men (YMSM)), (2) include within this context an evidence-based virtual intervention (e.g., promoting alcohol reduction), (3) instantiate and record a virtual choice (water or alcohol) in a virtual dating game scenario intervention with IA for that target audience, and (4) assess pre and 6-months post-intervention YMSM's alcohol use. Using a Socially Optimized Learning Environment (SOLVE) intervention game with IA and alcohol use measures, we found that virtual water choice (versus virtual alcohol choice) significantly predicted real-life alcohol consumption change. Furthermore, personality factors (e.g., Behavioral Approach System) predicted virtual choices and alcohol consumption change. Implications of these findings are discussed.

Causal Inference in Generalizable Environments: Systematic Representative Design.

Causal inference and generalizability both matter. Historically, systematic designs emphasize causal inference, while representative designs focus on generalizability. Here, we suggest a transformative synthesis - Systematic Representative Design (SRD) - concurrently enhancing both causal inference and "built-in" generalizability by leveraging today's intelligent agent, virtual environments, and other technologies. In SRD, a "default control group" (DCG) can be created in a virtual environment by representatively sampling from real-world situations. Experimental groups can be built with systematic manipulations onto the DCG base. Applying systematic design features (e.g., random assignment to DCG versus experimental groups) in SRD affords valid causal inferences. After explicating the proposed SRD synthesis, we delineate how the approach concurrently advances generalizability and robustness, cause-effect inference and precision science, a computationally-enabled cumulative psychological science supporting both "bigger theory" and concrete implementations grappling with tough questions (e.g., what is context?) and affording rapidly-scalable interventions for real-world problems.

Prefrontal Cortical Activity During the Stroop Task: New Insights into the Why and the Who of Real-World Risky Sexual Behavior.

Background: Research suggests that deficits in both executive functioning and trait impulsivity may play a role in risky sexual behavior. At the neural level, differences in regulation of the prefrontal cortex have been linked to impulsivity, measured neurocognitively and through self-report. The relationship between neurocognitive measures of executive control and trait impulsivity in predicting risky sexual behavior has not been investigated. Purpose: To investigate the relationship between neural functioning during the Stroop task and risky sexual behavior, as well as the effect of individual differences in urgent (positive and negative) impulsivity on this relationship. Methods: A total of 105 sexually active men who have sex with men completed the Stroop task during functional magnetic resonance imaging scanning. They also completed impulsivity inventories and self-reported their risky sexual behavior (events of condomless anal sex in the last 90 days). Results: Risky participants had greater activation than safe participants during the color congruent condition of the Stroop task in anterior cingulate cortex/dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, left frontal pole, and right insula. Across these regions, this neural activation mediated the link between (positive and/or negative) urgent impulsivity and risky sexual behavior. Conclusions: Findings suggest that the brains of men who engage in risky sexual behavior may employ a different distribution of cognitive resources during tasks of executive functioning than men who practice safe sex, and that this may relate to differences in the prefrontal cortical/fronto-insular system responsible for impulse control.

Oral Tolerance Development and Maintenance.

The gastrointestinal tract has an abundant mucosal immune system to develop and maintain oral tolerance. The oral route of administration takes advantage of the unique set of immune cells and pathways involved in the induction of oral tolerance. Food allergy results from a loss of oral tolerance toward ingested antigens. Oral immunotherapy is thought to initiate desensitization through interaction of an allergen with mucosal dendritic cells that initiate downstream immune system modulation through regulatory T cells and effector T cells.

A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders.

Allergen-specific type 2 helper T (TH2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic TH2 cell types. We have described a subset of human memory TH2 cells confined to atopic individuals that includes all allergen-specific TH2 cells. These cells are terminally differentiated CD4+ T cells (CD27- and CD45RB-) characterized by coexpression of CRTH2, CD49d, and CD161 and exhibit numerous functional attributes distinct from conventional TH2 cells. Hence, we have denoted these cells with this stable allergic disease-related phenotype as the TH2A cell subset. Transcriptome analysis further revealed a distinct pathway in the initiation of pathogenic responses to allergen, and elimination of these cells is indicative of clinical responses induced by immunotherapy. Together, these findings identify a human TH2 cell signature in allergic diseases that could be used for response-monitoring and designing appropriate immunomodulatory strategies.

Jug r 2-reactive CD4(+) T cells have a dominant immune role in walnut allergy.

BACKGROUND: Allergic reactions to walnut can be life-threatening. Although IgE epitopes of walnut have been studied, CD4(+) T cell-specific epitopes for walnut remain uncharacterized. In particular, the relationship of both phenotype and frequency of walnut-specific T cells to the disease have not been examined. OBJECTIVES: We sought to provide a thorough phenotypic analysis for walnut-reactive T cells in allergic and nonallergic subjects, particularly the relationship of phenotypes and frequencies of walnut-specific T cells with the disease. METHODS: The CD154 upregulation assay was used to examine CD4(+) T-cell reactivity toward the walnut allergens Jug r 1, Jug r 2, and Jug r 3. A tetramer-guided epitope mapping approach was used to identify HLA-restricted CD4(+) T-cell epitopes in Jug r 2. Direct ex vivo staining with peptide-major histocompatibility complex class II tetramers enabled comparison of the frequency and phenotype of Jug r 2-specific CD4(+) T cells between allergic and nonallergic subjects. Jug r 2-specific T-cell clones were also generated, and mRNA transcription factor levels were assessed by using quantitative RT-PCR. Intracellular cytokine staining assays were performed for further phenotypic analyses. RESULTS: Jug r 2 was identified as the major allergen that elicited CD4(+) T-cell responses. Multiple Jug r 2 T-cell epitopes were identified. The majority of these T cells in allergic subjects have a CCR4(+) phenotype. A subset of these T cells express CCR4(+)CCR6(+) irrespective of the asthmatic status of the allergic subjects. Intracellular cytokine staining confirmed these TH2-, TH2/TH17-, and TH17-like heterogenic profiles. Jug r 2-specific T-cell clones from allergic subjects mainly expressed GATA3, nonetheless, a portion of T-cell clones both GATA3 and RAR-related orphan receptor C (RORC) or RORC alone, confirming the presence of TH2, TH2/TH17, and TH17 cells. CONCLUSIONS: Jug r 2-specific responses dominate walnut T-cell responses in patients with walnut allergy. Jug r 2 central memory CD4(+) cells and terminal effector T cells were detected in peripheral blood, with the central memory phenotype as the most prevalent phenotype. In addition to conventional TH2 cells, TH2/TH17 and TH17 cells were also detected in nonasthmatic and asthmatic patients with walnut allergy. Understanding this T-cell heterogeneity might render better understanding of the disease manifestation.