Publications by authors named "Gregory T Moore"

18 Publications

  • Page 1 of 1

A Single Educational Intervention Improves Pregnancy-Related Knowledge and Emotional Health Among Women With IBD Who Are Pregnant or Wish to Conceive.

Inflamm Bowel Dis 2021 Mar 11. Epub 2021 Mar 11.

Department of Gastroenterology, St. Vincent's Hospital, Melbourne, Australia.

Background: There is considerable interest in improving the education and care of women with inflammatory bowel disease (IBD) to improve pregnancy outcomes. Despite increased awareness, not all women with IBD have access to pregnancy-related education and the quality of counseling is variable. We aimed to assess the effectiveness of a simple educational intervention for improving pregnancy-related knowledge and to evaluate the effect of education on patient outcomes including anxiety, depression, and quality of life in women with IBD.

Methods: This prospective study of women with IBD who were pregnant or planning a pregnancy evaluated the effectiveness of a single gastroenterologist-led educational intervention in improving pregnancy-related knowledge, measured using the Crohn's and Colitis Pregnancy Knowledge score 1 month postintervention. Secondary outcomes included the effect on anxiety and depression, quality of life, medication adherence, and patient satisfaction.

Results: One hundred women with IBD were recruited. Fifty percent were pregnant at the time of the intervention. Baseline knowledge scores were similar independent of the patients' pregnancy status or whether they had previously received counseling from their gastroenterologist. Median Crohn's and Colitis Pregnancy Knowledge scores postintervention (n = 82) were higher than preintervention scores (14/17 vs 10/17; P < 0.001). In addition, 32% of patients had poor knowledge at baseline (score ≤7/17), compared to only 5% after the intervention (P < 0.001). There was a significant improvement in total anxiety and depression and quality of life scores postintervention. Medication adherence and patient satisfaction were excellent.

Conclusions: Uptake of this gastroenterologist-led educational intervention has the potential to improve pregnancy knowledge, promote medication adherence, and enhance quality of life for women with IBD globally.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izab021DOI Listing
March 2021

Biosimilars: is interchangeability the proof of the pudding?

Med J Aust 2021 02 6;214(3):124-125. Epub 2021 Jan 6.

Monash Health, Melbourne, VIC.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5694/mja2.50912DOI Listing
February 2021

Infliximab, adalimumab and vedolizumab concentrations across pregnancy and vedolizumab concentrations in infants following intrauterine exposure.

Aliment Pharmacol Ther 2020 11 27;52(10):1551-1562. Epub 2020 Sep 27.

Fitzroy, VIC, Australia.

Background: The impact of pregnancy on levels of biologic agents in patients with IBD is undefined and time to elimination in vedolizumab-exposed infants is unknown.

Aims: To determine the effect of pregnancy on infliximab, adalimumab and vedolizumab levels and to study infant vedolizumab clearance METHODS: In a prospective observational study, maternal drug levels were measured pre-conception, in each trimester, at delivery and postpartum. The association between drug levels and gestation in weeks was assessed using generalised estimating equation modelling. Infant vedolizumab levels were performed at birth (cord blood), 6 weeks and 3 months or until undetectable.

Results: We included 50 IBD patients (23 on infliximab, 15 on adalimumab and 12 on vedolizumab) with at least two intrapartum observations, plus 5 patients on vedolizumab with only mother and baby samples at delivery. Modelling showed no change in adalimumab levels, an increase in infliximab levels of 0.16 (95% CI 0.08-0.24) µg/L/week (P < 0.001) and a decrease of 0.18 (95% CI: -0.33 to -0.02) µg/L/week (P = 0.03) for vedolizumab. In 17 mother-baby pairs, median infant vedolizumab levels at birth were lower than maternal levels (P < 0.05) with an infant:maternal ratio of 0.7 (IQR 0.5-0.9). Vedolizumab was undetectable between 15 and 16 weeks of age in all 12 infants completing follow-up testing.

Conclusions: During pregnancy, adalimumab levels remain stable, while infliximab levels increase and vedolizumab levels decrease. However, the increments were small suggesting that intrapartum therapeutic drug monitoring and dose adjustment are not indicated. Unlike infliximab and adalimumab, infant vedolizumab levels are lower in cord blood than in mothers and appear to clear rapidly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/apt.16102DOI Listing
November 2020

Psychological distress is highly prevalent in inflammatory bowel disease: A survey of psychological needs and attitudes.

JGH Open 2020 Apr 2;4(2):166-171. Epub 2019 Aug 2.

IBD Service, Department of Gastroenterology and Hepatology Royal Adelaide Hospital Adelaide South Australia Australia.

Background And Aim: Data on patient needs and access to psychological services in inflammatory bowel disease (IBD) are scarce. This study aimed to describe the levels of distress and the needs, attitudes, and access to psychological services for people within Australia against established Australian IBD Standards.

Methods: An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics, and the Royal Flying Doctor Service. K10 was used to measure psychological distress. The Chi-square test was used to compare those with and without distress on key variables.

Results: Overall, 731 respondents provided complete data (71.5% female, mean age 46.5 years). Overall, 50% of respondents reported distress; only 15.2% were currently seeing a mental health practitioner; only 16.1% were asked about their mental health by their IBD specialist or IBD nurse; and only 12.2% reported access to a mental health practitioner as part of their IBD service. Those with psychological distress were significantly less satisfied with their IBD care; more commonly hospitalized; had an active disease, fistula or perianal disease, pain, or fatigue; and were receiving steroids, opioids, or antidepressants (all  < 0.05). As many as 68.2% of those with severe distress were not seeing a mental health practitioner.

Conclusions: The integrated biopsychosocial model of health care, with regular mental health screening and good access to mental health professionals, is requested by people living with IBD to improve their outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgh3.12236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144796PMC
April 2020

Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue.

Gastroenterology 2020 07 10;159(1):169-182.e8. Epub 2020 Mar 10.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Victoria, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Victoria, Australia. Electronic address:

Background & Aims: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection.

Methods: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5 THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed.

Results: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P < .01), and correlated with gastritis severity (P < .05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5 THP-1 macrophages than by control THP-1 cells (P < .05). After 3 months of infection with H felis, Nlrc5 mice developed gastric hyperplasia (P < .0001), splenomegaly (P < .0001), and increased serum antibody titers (P < .01), whereas control mice did not. Nlrc5 mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P < .0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5 mice.

Conclusions: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2020.03.009DOI Listing
July 2020

Quality of care in inflammatory bowel disease: actual health service experiences fall short of the standards.

Intern Med J 2020 Oct;50(10):1216-1225

IBD Service, Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.

Background: Quality of care in inflammatory bowel disease (IBD) has received much attention internationally; however, the available surveys focus on health professionals rather than patients.

Aims: To assess the experiences of healthcare for people living with IBD against established Australian IBD Standards.

Methods: An online cross-sectional survey was conducted with Australians ≥16 years old recruited via Crohn's & Colitis Australia membership, public and private clinics and the Royal Flying Doctor Service. Participants completed a questionnaire incorporating items addressing the Australian IBD Standards 2016, the Picker Patient Experience Questionnaire, IBD Control Survey and the Manitoba Index.

Results: Complete data were provided by 731 respondents (71.5% female, median age 46 years, ranging from 16 to 84 years). While the majority (74.8%) were satisfied with their IBD healthcare, the care reported did not meet the Australian IBD Standards. Overall, 32.4% had access to IBD nurses, 30.9% to a dietician and 12% to a psychologist in their treating team. Participants managed by public IBD clinics were most likely to have access to an IBD nurse (83.7%), helpline (80.7%) and research trials (37%). One third of respondents reported waiting >14 days to see a specialist when their IBD flared. Participants received enough information, mostly from medical specialists (88.8%) and IBD nurses (79.4%). However, 51% wanted to be more involved in their healthcare.

Conclusions: These data show discordance between expectations of patients and national standards with current levels of service provision, which fail to deliver equitable and comprehensive IBD care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imj.14683DOI Listing
October 2020

Anti-TNF Therapy in Pregnant Women With Inflammatory Bowel Disease: Effects of Therapeutic Strategies on Disease Behavior and Birth Outcomes.

Inflamm Bowel Dis 2020 01;26(1):93-102

Department of Gastroenterology, St Vincent's Hospital, and University of Melbourne, Melbourne, Australia.

Background: Active inflammatory bowel disease (IBD) adversely affects pregnancy outcomes. Little is known about the risk of relapse after stopping anti-tumor necrosis factor (anti-TNF) treatment during pregnancy. We assessed the risk of relapse before delivery in women who discontinued anti-TNF treatment before gestational week (GW) 30, predictors of reduced infant birth weight, a marker associated with long-term adverse outcomes, and rates and satisfaction with counseling.

Methods: Pregnant women with IBD receiving anti-TNF treatment were prospectively invited to participate in an electronic questionnaire carried out in 22 hospitals in Denmark, Australia, and New Zealand from 2011 to 2015. Risk estimates were calculated, and birth weight was investigated using t tests and linear regression.

Results: Of 175 women invited, 153 (87%) responded. In women in remission, the relapse rate did not differ significantly between those who discontinued anti-TNF before GW 30 (1/46, 2%) compared with those who continued treatment (8/74, 11%; relative risk, 0.20; 95% confidence interval [CI], 0.02 to 1.56; P = 0.08). Relapse (P = 0.001) and continuation of anti-TNF therapy after GW 30 (P = 0.007) were independently associated with reduced mean birth weight by 367 g (95% CI, 145 to 589 g; relapse) and 274 g (95% CI, 77 to 471 g; anti-TNF exposure after GW 30). Of 134 (88%) women who received counseling, 116 (87%) were satisfied with the information provided.

Conclusions: To minimize fetal exposure in women in remission, discontinuation of anti-TNF before GW 30 seems safe. Relapse and continuation of anti-TNF therapy after GW 30 were each independently associated with lower birth weight, although without an increased risk for birth weight <2500 g. Most women received and were satisfied with counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ibd/izz110DOI Listing
January 2020

Crohn's & Colitis Australia inflammatory bowel disease audit: measuring the quality of care in Australia.

Intern Med J 2019 07;49(7):859-866

Gastroenterology and Hepatology Unit, The Canberra Hospital, Canberra, Australian Capital Territory, Australia.

Background: Australia has among the highest prevalence of Crohn disease and ulcerative colitis in the world. Management of the chronic gastrointestinal disorders results in significant societal costs and the standard of care is inconsistent across Australia.

Aim: To audit the quality of care received by patients admitted for inflammatory bowel disease (IBD) across Australia against national IBD standards.

Methods: A retrospective cross-sectional survey and clinical audit was undertaken assessing organisational resources, clinical processes and outcome measures. This study was conducted in Australian hospitals that care for inpatients with Crohn disease or ulcerative colitis. The main outcome measures were adherence to national IBD standards and comparison of quality of care between hospitals with and without multidisciplinary IBD services.

Results: A total of 71 hospitals completed the organisational survey. Only one hospital had a complete multidisciplinary IBD service and 17 had a partial IBD service (IBD nurse, helpline and clinical lead). A total of 1440 inpatient records was reviewed from 52 hospitals (mean age 37 years; 51% female, 53% Crohn disease), approximately 26% of IBD inpatient episodes over a 12-month period in Australia. These patients were chronically unwell with high rates of anaemia (30%) and frequent readmissions (40% within 2 years). In general, care was inconsistent, and documentation was poor. Hospitals with a partial IBD service performed better in many processes and outcome measures: for example, 22% reduction in admissions through emergency departments and greater adherence to standards for safety monitoring of biological (89% vs 59%) and immunosuppressive drugs (79% vs 55%) in those hospitals than those without.

Conclusion: Patients admitted to hospital suffering from IBD are young, chronically unwell and are subject to substantial variations in clinical documentation and quality of care. Only one hospital met accepted standards for multidisciplinary care; hospitals with even a minimal IBD service provided improved care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imj.14187DOI Listing
July 2019

Immunomodulator use does not prevent first loss of response to anti-tumour necrosis factor alpha therapy in inflammatory bowel disease: long-term outcomes in a real-world cohort.

Intern Med J 2019 06;49(6):753-760

Department of Gastroenterology and Hepatology, Monash Medical Centre, Melbourne, Victoria, Australia.

Background: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited.

Aim: To assess whether anti-tumour necrosis factor alpha (anti-TNF) monotherapy was associated with earlier loss of response (LOR) than combination therapy in a real-world cohort with long-term follow up.

Methods: A retrospective audit was conducted of inflammatory bowel disease patients receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients with accurate data for anti-TNF commencement and adequate correspondence to determine end-points were included. Outcomes measured included time to first LOR, causes and biochemical parameters.

Results: Two hundred and twenty-four patients were identified; 139 (62.1%) on combination therapy and 85 (37.9%) on monotherapy. Forty-five percent of patients had LOR during follow up until a maximum of 8.5 years; 59.4% on combination therapy and 40.6% on monotherapy (P = 0.533). The median time to LOR was not different between groups; 1069 days for combination therapy and 1489 days for monotherapy (P = 0.533). There was no difference in time to LOR between patients treated with different combination regimens or different anti-TNF agents.

Conclusion: In this large cohort of patients in a real-world setting, patients treated with anti-TNF monotherapy had similar rates of LOR as patients on anti-TNF combination therapy, at both short- and long-term follow up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imj.14150DOI Listing
June 2019

Crohn's and Colitis Australia Inflammatory Bowel Disease Audit: Identifying disaster in waiting.

Authors:
Gregory T Moore

J Gastroenterol Hepatol 2018 Sep;33 Suppl 3:33-34

Inflammatory Bowel Disease, Gastroenterology and Hepatology Unit, Monash Medical Centre, Melbourne, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.14436DOI Listing
September 2018

Buruli (Bairnsdale) ulcer in the setting of long-term adalimumab treatment for Crohn disease.

Intern Med J 2018 05;48(5):603-604

School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/imj.13788DOI Listing
May 2018

Predicting response after infliximab salvage in acute severe ulcerative colitis.

J Gastroenterol Hepatol 2018 Jul 27;33(7):1347-1352. Epub 2018 Feb 27.

Department of Gastroenterology, Austin Health, Melbourne, Australia.

Background And Aim: Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15 years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification.

Methods: Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12 months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared.

Results: Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3 months and 26.92% (14/52) at 12 months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P = 0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage.

Conclusions: The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.14072DOI Listing
July 2018

Weight and Body Composition Compartments do Not Predict Therapeutic Thiopurine Metabolite Levels in Inflammatory Bowel Disease.

Clin Transl Gastroenterol 2016 Oct 27;7(10):e199. Epub 2016 Oct 27.

Department of Gastroenterology & Hepatology, Monash Health, Clayton, Australia.

Objectives: Thiopurine drugs are the most commonly used steroid-sparing therapies in moderate-to-severe inflammatory bowel disease (IBD). Their complex metabolism and their narrow therapeutic windows means that optimal dosing is difficult. However, weight-based dosing is the norm. Similar antimetabolites are dosed by body composition parameters. In IBD, treatment response and toxicity has been shown to correlate with thiopurine metabolite levels. We sought to determine whether weight or body composition parameters predicted therapeutic 6-thioguanine nucleotide (6TGN) or toxic 6-methylmercaptopurine (6MMP) levels.

Methods: This single-center retrospective cohort study identified 66 IBD patients who had body composition analysis and thiopurine metabolite levels tested. Statistical analysis was performed using Spearman correlation, Kruskal-Wallis, Mann-Whitney, and unpaired t tests and receiver-operator operating characteristic curves. A P value of <0.05 was considered significant.

Results: No correlation was identified between 6TGN and any body composition parameters, absolute drug dose or drug dose/kg of fat mass, fat-free mass (FFM), subcutaneous adipose tissue area, or visceral adipose tissue area. However, 6MMP correlated with azathioprine dose, thiopurine dose/kg of body weight, and with several body composition parameters.

Conclusions: No relationship was found between therapeutic metabolite levels and weight or body composition compartments. Higher thiopurine doses, especially in relation to FFM, are associated with higher levels of potentially hepatotoxic 6MMP and shunting toward this metabolite. Conventional weight-based dosing to attain therapeutic metabolite levels appears unreliable and may be replaced by metabolite level testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ctg.2016.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288590PMC
October 2016

Biosimilars in inflammatory bowel disease.

Authors:
Gregory T Moore

Med J Aust 2016 Oct;205(7):294-5

Monash Health, Clayton, VIC

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5694/mja16.00775DOI Listing
October 2016

Achieving and maintaining quality of care in inflammatory bowel disease: The Crohn's and Colitis Australia audit.

Authors:
Gregory T Moore

J Gastroenterol Hepatol 2016 Jun;31 Suppl 1:39

Monash Health & School of Clinical Sciences, Monash University, Crohn's and Colitis Australia, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.13367DOI Listing
June 2016

Relationship between disease severity and quality of life and assessment of health care utilization and cost for ulcerative colitis in Australia: a cross-sectional, observational study.

J Crohns Colitis 2014 Jul 15;8(7):598-606. Epub 2013 Dec 15.

Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. Electronic address:

Background & Aims: The burden of ulcerative colitis (UC) in relation to disease severity is not well documented. This study quantitatively evaluated the relationship between disease activity and quality of life (QoL), as well as health care utilization, cost, and work-related impairment associated with UC in an Australian population.

Methods: A cross-sectional, noninterventional, observational study was performed in patients with a wide range of disease severity recruited during routine specialist consultations. Evaluations included the Assessment of Quality of Life-8-dimension (AQoL-8D), EuroQol 5-dimension, 5-level (EQ-5D-5L), the disease-specific Inflammatory Bowel Disease Questionnaire (IBDQ), and the Work Productivity and Activity Impairment (WPAI) instrument. The 3-item Partial Mayo Score was used to assess disease severity. Health care resource utilization was assessed by chart review and patient questionnaires.

Results: In 175 patients, mean (SD) AQoL-8D and EQ-5D-5L scores were greater for patients in remission (0.80 [0.19] and 0.81 [0.18], respectively) than for patients with active disease (0.70 [0.20] and 0.72 [0.19], respectively, both Ps<0.001). IBDQ correlated with both AQoL-8D (r=0.73; P<0.0001) and EQ-5D-5L (0.69; P<0.0001). Mean 3-month UC-related health care cost per patient was AUD $2914 (SD=$3447 [mean for patients in remission=$1970; mild disease=$3736; moderate/severe disease=$4162]). Patients in remission had the least work and activity impairment.

Conclusions: More severe UC disease was associated with poorer QoL. Substantial health care utilization, costs, and work productivity impairments were found in this sample of patients with UC. Moreover, greater disease activity was associated with greater health care costs and impairment in work productivity and daily activities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.crohns.2013.11.017DOI Listing
July 2014

Glycosylation changes in hFUT1 transgenic mice increase TCR signaling and apoptosis resulting in thymocyte maturation arrest.

Mol Immunol 2008 Apr 26;45(8):2401-10. Epub 2007 Dec 26.

Immunology Research Centre, St. Vincent's Hospital Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia.

Glycosylation of cell surface proteins is important in thymocyte maturation. In particular, the level of sialylation of key glycoproteins such as CD45 is believed to play a major role in regulating TCR signaling, adhesion and apoptosis of developing thymocytes. We show here that transgenic expression of human alpha1-2 fucosyltransferase (hFUT1) in mice resulted in a marked shift from sialylation to fucosylation of thymocyte glycoproteins. This was associated with a significant reduction in thymocyte number, an increased rate of apoptosis in double positive and single positive thymocytes, and a maturation arrest at TCR-dependent developmental transitions reminiscent of CD45 deficiency. Indeed, CD45RB dimerization was elevated in hFUT1 thymocytes, consistent with its hyposialylation, and there was a corresponding increase in phosphorylation of the TCR-associated protein Lck. However, contrary to the reduced TCR signaling in CD45 null mice, basal and stimulated TCR signaling was higher in hFUT1 thymocytes than in wild type thymocytes. Our results therefore demonstrate that aberrant expression of a single glycosyltransferase can profoundly affect thymopoiesis, although the relative involvement of CD45-dependent and -independent mechanisms is yet to be determined.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molimm.2007.11.006DOI Listing
April 2008

Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice.

Inflamm Bowel Dis 2004 Sep;10(5):546-56

Immunology Research Centre, St. Vincent's Hospital, Fitzroy, Victoria 3056, Australia.

Background And Aims: Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis.

Methods: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated.

Results: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice.

Conclusion: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/00054725-200409000-00008DOI Listing
September 2004