Browsing by Subject "Tolerance"
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Item A critical review of front-loading: A maladaptive drinking pattern driven by alcohol's rewarding effects(Wiley, 2022) Ardinger, Cherish E.; Lapish, Christopher C.; Czachowski, Cristine L.; Grahame, Nicholas J.; Psychology, School of ScienceFront‐loading is a drinking pattern in which alcohol intake is skewed toward the onset of reward access. This phenomenon has been reported across several different alcohol self‐administration protocols in a wide variety of species, including humans. The hypothesis of the current review is that front‐loading emerges in response to the rewarding effects of alcohol and can be used to measure the motivation to consume alcohol. Alternative or additional hypotheses that we consider and contrast with the main hypothesis are that: (1) front‐loading is directed at overcoming behavioral and/or metabolic tolerance and (2) front‐loading is driven by negative reinforcement. Evidence for each of these explanations is reviewed. We also consider how front‐loading has been evaluated statistically in previous research and make recommendations for defining this intake pattern in future studies. Because front‐loading may predict long‐term maladaptive alcohol drinking patterns leading to the development of alcohol use disorder (AUD), several future directions are proposed to elucidate the relationship between front‐loading and AUD.Item Adult-onset mast cell activation syndrome following scombroid poisoning: a case report and review of the literature(BMC, 2021-12-18) Brock, Isabelle; Eng, Nicole; Maitland, Anne; Medical and Molecular Genetics, School of MedicineBackground: Mast cells are closely associated with epithelium, serving as sentinels responsible for the recognition of tissue injury and coordination of the initial inflammatory response. Upon detection of the injured cell content, mast cells then tailor the release of preformed and newly produced chemical mediators to the detected challenge, via an array of pathogen receptors. In addition to immunoglobulin E receptor-triggered mast cell activation, commonly referred to as allergic or atopic disorders, non-immunoglobulin E receptor mediated mast cell activation follows engagement of toll-like receptors, immunoglobulin G receptors, and complement receptors. Upon containment of the extrinsic challenge, acute inflammation is downregulated, and repair of the injured tissue ensues. The mast cell compartments must return to a baseline steady state to remain tolerant towards self-antigens and harmless entities, including environmental conditions, to prevent unnecessary immune activation and chronic hypersensitivity disorders. Over the past 50 years, an increasing number of patients are experiencing episodes of aberrant mast cell activation, not associated with allergen-specific mast cell disease or systemic mastocytosis. This led to proposed diagnostic criteria of mast cell activation syndrome. Mast cell activation syndrome is a heterogeneous disorder, defined by a combination of (1) recurrent symptoms typical of mast cell activation, (2) an increase of validated mast cell derived mediators, and (3) response to treatment with mast cell stabilizing or mast cell mediator-targeted therapies. Onset of mast cell activation syndrome ostensibly reflects the loss of tolerance in the mast cell compartment to nonthreatening entities and nonhazardous environmental conditions. The etiology of chronic mast cell dysregulation and associated intolerance to self-antigens or harmless entities is not well understood, but a growing number of studies point to exposure of the epithelial borders, which leads to inappropriate or excessive mast cell activation or impaired resolution of acute inflammation following neutralization of the identified pathogen. Case presentation: Here we present a case of adult onset mast cell activation syndrome following scombroid poisoning. Scombroid toxicity is usually a self-limited illness, but there are individuals who have been shown to have severe symptoms or persistent illness following histamine fish poisoning. We describe a 74-year-old Caucasian woman, with a history of drug-induced urticaria, who developed a constellation of hypersensitivity illnesses consistent with the diagnosis of mast cell activation syndrome after ingestion of tainted fish. Conclusion: Mast cell activation disease causes problems of increased complexity in children and adults. The increased prevalence and severity of mast cell activation disease has been attributed to dramatic changes in our lifestyles and modern living environments. These changes likely impact the integrity of the epithelial barriers, leading to loss of tolerance in the mast cell compartment. Here, we present a case of a nonatopic, 74-year-old female who developed mast cell activation disease after exposure to a potent environmental toxin. Mast cell activation disease commonly involves several organ systems, with patients often referred to a succession of different specialists. This results in delayed diagnosis and suboptimal care. Instead, early recognition of mast cell activation disease would lead to better outcomes. We review the literature, describing the diagnostic criteria for mast cell activation disorders that can improve recognition of this multiorgan system syndrome. Further research is needed into the interaction of epithelial barrier disruption and the dysregulation of the immune system.Item CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII(Elsevier, 2021) Rana, Jyoti; Perry, Daniel J.; Kumar, Sandeep R.P.; Muñoz-Melero, Maite; Saboungi, Rania; Brusko, Todd M.; Biswas, Moanaro; Pediatrics, School of MedicineRegulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-specific manner. This capacity can now be harnessed for tolerance induction by "redirecting" polyclonal Tregs to overcome low inherent precursor frequencies and simultaneously augment suppressive functions. With the use of hemophilia A as a model, we sought to engineer antigen-specific Tregs to suppress antibody formation against the soluble therapeutic protein factor (F)VIII in a major histocompatibility complex (MHC)-independent fashion. Surprisingly, high-affinity chimeric antigen receptor (CAR)-Treg engagement induced a robust effector phenotype that was distinct from the activation signature observed for endogenous thymic Tregs, which resulted in the loss of suppressive activity. Targeted mutations in the CD3ζ or CD28 signaling motifs or interleukin (IL)-10 overexpression were not sufficient to restore tolerance. In contrast, complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRuC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response. These data suggest that cellular therapies employing engineered receptor Tregs will require regulation of activation thresholds to maintain optimal suppressive function.Item Developmental differences in hypothermic and behavioral responses to ethanol treatment in Alcohol Preferring and Non-Preferring Rats(2012-08-30) Myers, Mallory Lynn; Goodlett, Charles R.; Murphy, James M.; Bell, Richard L.Differences in voluntary consumption of ethanol have been negatively correlated with differences in initial sensitivity and tolerance to ethanol’s pharmacological effects. From this perspective, both adolescent and adult alcohol-nonpreferring (NP) rats would be expected to be initially more sensitive to the sedative and hypothermic effects of ethanol and fail to acquire tolerance to those effects than preferring (P) rats. The first objective of this experiment was to assess alcohol-induced hypothermia and locomotor sedation in adolescent and adult P and NP rats over five consecutive daily administrations (saline, 1.5 g/kg, or 3.0 g/kg ethanol 17%v/v), testing the hypothesis that the P rats would acquire tolerance to the hypothermic response whereas the NP rats would not show changes across days. In addition, it was hypothesized that there would be age-related differences in initial sensitivity to ethanol, evident by adolescent rats displaying less ethanol-induced hypothermia and locomotor sedation than adult rats on Day 1. The second objective was to determine if conditioning was occurring between the administration environment and the hypothermic response and locomotor sedation elicited by ethanol exposure, via a sixth injection of saline. Female rats were surgically implanted with intraperitoneal Mini Mitter telemetry probes on postnatal day 25 or 85 and experimental manipulations began five days later. Data were collected every minute; temperature data were then converted to change from baseline scores and locomotor data were totaled for each session. On Day 1, maximum temperature reduction elicited by the 3.0 g/kg dose was greater in the NP rats than the P rats, regardless of age. That dose also produced greater levels of locomotor sedation in the adult rats compared to the adolescent rats, regardless of line. The 1.5 g/kg dose of ethanol produced a greater hypothermic response in adult rats compared to adolescent rats, locomotor activity was reduced equally across the groups. With repeated administrations, NP adult rats displayed sensitization to the hypothermic response elicited from the 3.0 g/kg dose; in contrast, tolerance to the hypothermic response was found within the 1.5 g/kg dose for the adolescent P, adult P, and the adult NP rats. Repeated saline administrations also resulted in tolerance to the hypothermic response associated with administration in the adult NP and adolescent P rats. On the Day 6 saline administrations, adult rats which had previously been exposed to the 3.0 g/kg dose, maintained their baseline body temperatures better than both of the other exposure groups. Adolescent rats failed to show any signs of conditioning when administered saline on Day 6. Contrary to prediction the P rats failed to acquire tolerance to the 3.0 g/kg dose for either measure; and the line difference in ethanol-induce hypothermia was due to sensitization of the hypothermic response in adult NP rats. These results also provide further support that adolescent rats are less sensitive to the initial aversive effects of ethanol at the 1.5 g/kg dose for ethanol-induced hypothermia and the 3.0 g/kg dose for locomotor activity. The current experiment provides evidence that initial sensitivity as well as the acquisition of tolerance to ethanol-induced hypothermia may be behavioral phenotypes correlated with selection for high and low alcohol drinking preference.Item Drinking Rhythms in Alcohol Preferring Mice(2012-08-29) Matson, Liana M.; Grahame, Nicholas J.; Czachowski, Cristine; Boehm II, Stephen L.Multiple lines of High Alcohol Preferring (HAP) mice were selectively bred for their intake of 10% ethanol (v/v) during 24-h daily access over a four-week period, with the highest drinking lines exhibiting intakes in excess of 20 g/kg/day. Drinking rhythms and corresponding blood ethanol concentrations (BEC) of the highest drinking HAP lines to those of the C57BL/6J (B6) inbred strain. Adult male and female crossed HAP (cHAP), HAP1 and B6 mice had free-choice access to 10% ethanol and water for 3 weeks prior to bi-hourly assessments of intake throughout the dark portion of a reverse 12:12 light dark cycle. In another cohort of cHAP mice, the same procedure was used to assess bi-hourly ethanol intake, and blood samples were taken across the day to look at the pattern of accumulation in these mice. Finally, considering the high level of intake by cHAP mice, we were interested in assessing whether metabolic and functional tolerance develop following chronic free-choice access, which were assessed using 2.0 and 1.75 g/kg challenge doses of 20% ethanol, respectively. cHAP and HAP1 mice maintained an excessive level of intake throughout the dark portion of the cycle, accumulating mean BEC levels of 261.5 + 18.09 and 217.9 + 25.02 mg/dl at 7-8 hours following lights off, respectively. B6 mice drank comparatively modestly, and did not accumulate high BEC levels (53.63 + 8.15 mg/dl). In the cHAP cohort, mean BECs were 112.47 + 19.91 at 2 hours after lights off, 189.00 + 27.40 at 6 hours after lights off, 193.80 + 29.66 at 10 hours after lights off, and 89.68 + 22.19 at 2 hours after lights on. Further, following 3 weeks of ethanol access, cHAP mice had a faster rate of ethanol metabolism and fewer hind slips than water-only exposed mice (ps < .05). In conclusion, the excessive free-choice drinking demonstrated by the HAP1 and cHAP lines, as well as the pattern of sustained high BECs in cHAP mice, challenge the notion that rodents will not reliably and voluntarily sustain ethanol intake at pharmacologically relevant levels. These results suggest that the highest drinking HAP lines may provide a unique opportunity for modeling the excessive intake that has been observed in alcohol-dependent individuals. Further, we observed that cHAP mice develop both metabolic and functional tolerance to the ataxic effects of ethanol following 3 weeks of free-choice access. Together, these findings support HAP mice as translational rodent model of alcoholism, and provide rationale for exploration of the predisposing factors for excessive consumption, as well as the development of physiological, behavioral, and toxicological outcomes following alcohol exposure.Item Drosophila homer is required in a small set of neurons including the ellipsoid body for normal ethanol sensitivity and tolerance(Society for Neuroscience, 2007-04-25) Urizar, Nancy L.; Yang, Zhiyong; Edenberg, Howard J.; Davis, Ronald L.; Biochemistry and Molecular Biology, School of MedicineThe molecular mechanisms occurring in the nervous system that underlie behavioral responses to ethanol remain poorly understood. Here, we report that molecular requirements for two of these responses, initial sensitivity and the development of rapid tolerance, comap to the same small set of neurons. We show that null homer mutant flies exhibit both increased sensitivity to the sedative effects of ethanol and failure to develop normal levels of rapid tolerance. Both the sensitivity and rapid tolerance phenotypes of the homer mutants are rescued by the expression of wild-type homer in a subset of neurons that include the ellipsoid body. Thus, some of the molecular- and systems-level requirements for these two behavioral responses to ethanol are identical.Item La enseñanza de temas homosexuales en la literatura: El fomento de un multiculturalismo más completo en los estudios de la literatura española(2013-11-12) Cobb, Vaughn Aaron; Brant, Herbert J.; Ardemagni, Enrica J.; Torijano, J. Agustín, 1963-A variety of minority groups are present in the readings of Spanish and Latin American literature classes; however, there is a lack of representation of homosexual themes in the readings. This paper takes a look at what homosexual themes are present in the literature anthologies in current use, and then suggest a teaching unit and methodology for how one can implement these topics into a literature class. The paper provides a sound basis for teachers who are trying to introduce these issues into their classes. [Language - Spanish]Item Offspring of parents with an alcohol use disorder prefer higher levels of brain alcohol exposure in laboratory experiments involving computer-assisted self-infusion of ethanol (CASE)(SpringerLink, 2009-03) Zimmermann, Ulrich S.; Mick, Inge; Laucht, Manfred; Vitvitskiy, Victor; Plawecki, Martin H.; Mann, Karl F.; O’Connor, Sean; Psychiatry, School of MedicineRationale: Acute alcohol effects may differ in social drinkers with a positive family history of alcohol use disorders (FHP) compared to FH negative (FHN) controls. Objectives: To investigate whether FHP subjects prefer higher levels of brain alcohol exposure than do FHN controls. Materials and methods: Twenty-two young healthy nondependent social drinkers participated in two identical sessions of computer-assisted self-infusion of ethanol (CASE); the first for practicing the procedures, the second to test hypotheses. All 12 FHP (four women) and ten FHN (three women) participants received a priming exposure, increasing arterial blood alcohol concentration (aBAC) to 30 mg% at 10 min and decreasing it to 15 mg% at 25 min. A 2-h self-administration period followed, during which only the subjects could increase their aBAC by pressing a button connected to a computer controlling the infusion pump. Infusion rate profiles were calculated instantaneously to increase aBAC by precisely 7.5 mg% within 2.5 min after each button press, followed by a steady descent. Subjects were instructed to produce the same alcohol effects as they would do at a weekend party. Results: The mean and maximum aBAC during the self-administration period and the number of alcohol requests (NOAR) were significantly higher in the FHP vs. FHN participants. Conclusions: This is the first laboratory experiment demonstrating higher alcohol self-administration in FHP compared to FHN subjects. A practice session increases the sensitivity of CASE experiments for detection of subtle differences in human alcohol self-administration.Item Pluralism in Muslim American Philanthropy Report 2022(Muslim Philanthropy Initiative, Lilly Family School of Philanthropy, 2022-09-08) Siddiqui, Shariq; Hughes, Micah; Wasif, Rafeel; Paarlberg, Afshan; Cheema, Jehanzeb; Samad, Abdul; Noor, ZeeshanThe Pluralism in Muslim American Philanthropy 2022 Report shows that, on average, U.S. Muslims surveyed perceived themselves to have higher levels of characteristics such as tolerance, valuing diversity and racial inclusivity, religiosity, and motivation to donate to causes benefitting people with marginalized identities (described in the study as “donation motivation”) than U.S. non-Muslims perceived themselves to have. This report details the findings on pluralism and tolerance perception from a self-administered web survey conducted by SSRS for the Indiana University Lilly Family School of Philanthropy. The larger study, of which these findings are a part, surveys the opinions of Muslims and the general population regarding faith customs, donation practices and attitudes, volunteer work, remittances, and zakat. SSRS conducted its survey from January 25 through February 15, 2022 with 2,010 adult respondents (age 18 and over), including 1,024 Muslim and 960 general population respondents. SSRS reached eligible respondents via a nonprobability web panel sample.Item The regulation of allergic airway disease by type V collagen-induced tolerance(2013-12-11) Lott, Jeremy M.; Wilkes, David S.; Kaplan, Mark H.; Smith, Gerald N.; Vasko, Michael R.; Blum, Janice Sherry, 1957-Rationale: Tissue remodeling and complement activation are asthma hallmarks. Type V collagen [col(V)], a cryptic antigen, becomes exposed during lung remodeling. IL-17 is key to anti-col(V) immunity, and regulates complement activation. We have reported that col(V)-induced tolerance down regulates IL-17 and prevents immune-mediated lung diseases. Objectives: Determine a role for anti-col(V) immunity in asthma. Methods: Serum anti-col(V) antibodies were measured in asthma patients, and immunohistochemistry utilized to detect interstitial col(V) in fatal asthma. Balb/c mice were tolerized with col(V) prior to sensitization with ovalbumin (OVA), and subsequent OVA intranasal challenge. Airway hyper-responsiveness (AHR) to methacholine was measured; and RT-PCR utilized to determine local Il17 transcripts. Bronchoalveolar lavage levels of C3a¸ C5a and OVA-specific IgE were measured; and immunohistochemistry utilized to detect expression of complement regulatory proteins, expression, CD46/Crry and CD55, in lung tissue. Results: Compared to normal subjects, anti-col(V) antibodies were increased in asthmatics; and interstitial col(V) was over expressed in fatal asthma. OVA-induced AHR up regulated anti-col(V) antibodies systemically, and increased OVA-specific IgE and C3a in BAL, and parenchymal Il17 transcripts. Col(V)-induced tolerance abrogated AHR, down regulated OVA-induced T cell proliferation, as well as total and OVA-specific IgE, C3a, IL-17 expression and tracheal smooth muscle contraction. Crry/CD46 and CD55, key to preventing complement activation, were down regulated on goblet cells in murine allergic airway disease. Conclusions: Anti-col(V) immunity correlates with asthma pathogenesis, and col(V)-induced tolerance may be a novel therapeutic for asthma. Decreased expression of Crry/CD46 and CD55 on goblet cells may in part account for complement activation in asthma.