[Show abstract][Hide abstract] ABSTRACT: Human monocyte-derived DC (MoDC) are utilised for immunotherapy. However, in vitro immunological effects are often not mirrored in vivo. We studied tissue homing potential of MoDC. Circulating monocytes and DC expressed different tissue homing markers and during in vitro development of MoDC homing marker expression was lost resulting in a "homeless" phenotype. Retinoic acid (RA) induced gut-homing markers (β7 and CCR9) and a regulatory phenotype and function (decreased HLA-DR and increased ILT3 and FITC-Dextran uptake) in MoDC. RA-MoDC were less stimulatory and primed conditioned T-cells with a gut-homing profile (β7(+) CLA(-) ). Unlike normal intestinal microenvironment, that from inflamed colon of ulcerative colitis (UC) patients did not induce regulatory properties in MoDC. However, RA-MoDC maintained their regulatory gut-specific properties even in the presence of UC microenvironment. Therefore, MoDC may be ineffectual for immunotherapy because they lack tissue homing and tissue-imprinting specificity. However, MoDC rehabilitation with gut-homing potential by RA could be useful in promoting immunotherapy in pathologies like UC.
[Show abstract][Hide abstract] ABSTRACT: Background. Dendritic cells regulate immune responses to microbial products and play a key role in ulcerative colitis (UC) pathology. We determined the immunomodulatory effects of probiotic strain Lactobacillus casei Shirota (LcS) on human DC from healthy controls and active UC patients. Methods. Human blood DC from healthy controls (control-DC) and UC patients (UC-DC) were conditioned with heat-killed LcS and used to stimulate allogeneic T cells in a 5-day mixed leucocyte reaction. Results. UC-DC displayed a reduced stimulatory capacity for T cells (P < 0.05) and enhanced expression of skin-homing markers CLA and CCR4 on stimulated T cells (P < 0.05) that were negative for gut-homing marker β7. LcS treatment restored the stimulatory capacity of UC-DC, reflecting that of control-DC. LcS treatment conditioned control-DC to induce CLA on T cells in conjunction with β7, generating a multihoming profile, but had no effects on UC-DC. Finally, LcS treatment enhanced DC ability to induce TGFβ production by T cells in controls but not UC patients. Conclusions. We demonstrate a systemic, dysregulated DC function in UC that may account for the propensity of UC patients to develop cutaneous manifestations. LcS has multifunctional immunoregulatory activities depending on the inflammatory state; therapeutic effects reported in UC may be due to promotion of homeostasis.
Mediators of Inflammation 01/2013; 2013:573576. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IntroductionPrevious reports suggest tacrolimus is effective for induction of remission in refractory inflammatory bowel disease (IBD).1 There are limited data regarding the long term outcomes of tacrolimus for inflammatory bowel disease. The authors reviewed the long term experience of patients treated with tacrolimus at a tertiary centre.Methods
In this retrospective, single centre study the authors reviewed the clinical records of 18 adult patients between 2006 and 2010 with refractory IBD (UC 9; CD 8; Pouchitis 1) treated with oral tacrolimus. Clinical activity was evaluated using modified Truelove and Witts Score (mTW), CDAI and PDAI respectively. Response and remission were considered mTW reduction ≥50%/
[Show abstract][Hide abstract] ABSTRACT: IntroductionAnimal studies have shown that glucagon like peptide-2 (GLP-2) may reduce mucosal inflammation; it decreases proinflammatory cytokines and ameliorates chronic colitis1. However, we do not yet know whether this anti-inflammatory effect occurs in humans. If so, it potentially opens the door for use of GLP-2 as therapy in conditions like inflammatory bowel disease. Therefore we studied the immunomodulatory functions of GLP-2 in humans.Methods
Dendritic cells (DC) enriched from human blood of healthy volunteers were cultured in-vitro for 24 h with GLP-2 at concentrations of 1 pM, 1 nM and 1 mM. The effect of GLP-2 on DC survival was determined using apoptosis experiments. Phenotype and functions of DC were then assessed by flow cytometry and mixed leucocyte reaction (MLR), respectively. Each experiment was performed independently at least 3 times and analysed for statistically significant effects.ResultsApoptosis experiments showed that GLP-2 at all concentrations did not have a toxic effect on DC; their survival after in-vitro culture with GLP-2 was similar to that in basal control culture (p=NS). GLP-2 conditioning changed the phenotype of DC with reduction in HLA-DR intensity (p=0.0243) and increase in CD14 expression (p=0.0237), compared with basal control culture. However, the down-regulation of HLA-DR intensity and up-regulation of CD14 expression did not correlate with an increase in the phagocytic capacity (p=NS). Other markers of immature DC, ILT3 and DC SIGN, were not affected. TLR2/4 expression was also not affected by the treatment (p=NS). Finally, MLR experiments showed that GLP-2 treatment on DC did not have an effect on their stimulation of T cell proliferation (p=NS).ConclusionGLP-2 reduced HLA-DR and increased CD14 on DCs, though this effect does not correlate with T-cell stimulation in-vitro. More studies are needed to detect any functional significance to the changes GLP-2 induced on dendritic cells.
[Show abstract][Hide abstract] ABSTRACT: IntroductionImmunomodulators (IM) and biological agents are now used more often and earlier in Inflammatory Bowel Disease (IBD), leading to an increase in opportunistic infections (OI). The RR of OI is reported as OR of 2.9 with one IM, increasing to OR of 14.5 with ≥2 concomitant IMs. Age (>50 years) is also an independent risk factor for OI. These vaccinations are recommended by the European Crohn's and Colitis Organisation (ECCO) to minimise OI in immunocompromised IBD patients; Varicella Zoster Virus (VZV) (if no history of chickenpox/shingles and serology is negative), Human Papilloma Virus (HPV), annual Influenza (inactivated vaccine), Pneumococcal and Hepatitis B (if HBV seronegative). Following the Influenza A outbreak (H1N1) in 2009, Swine Flu vaccination was also recommended. The authors aimed to investigate the vaccination status of IBD patients on one or more IM.Methods
The authors identified a cohort of 200 patients on IM or biological therapy from outpatients attendance between September 2009 and June 2010. Questionnaires were posted to the General Practitioners (GP) to obtain vaccination status for Flu (within 1 year), Pneumococcal (within last 5 years), VZV, HPV and Swine Flu. T test was used to examine for differences in higher risk groups.ResultsThe response rate was 51.5% (103/200). Median age was 42 years (range 16–74); 54 were female (52.4%). 82 were tertiary referrals (79.6%). 75.7% had Crohn's disease (n=78). IMs included Azathioprine (35.9%, n=37), 6-Mercaptopurine (9.7%, n=10), corticosteroids (5.8%, n=6), Methotrexate (3.8%, n=4) and Tacrolimus (1.9%, n=2). Biological agents included Infliximab (36.9%, n=38) and Adalimumab (25.2%, n=26).PTH-063 Administered vaccinationsNot administered (n (%))VaccineAdministered (n (%)Not invitedPatient refusedUnknown status (n (%))Not eligible (n (%))Flu38 (36.9)56 (54.4)9 (8.7)0 (0)0 (0)H1N133 (32.0)60 (58.3)9 (8.7)0 (0)1 (0.9)*Pneumococcal7 (6.8)91 (88.3)4 (3.4)1 (0.9)0 (0)HPV0 (0)14 (13.6)0 (0)1 (0.9)88 (85.4)VZV0 (0)72 (70.0)0 (0)7 (6.7)24 (23.3)*Patient previously contracted illness, not eligible for vaccination.21 patients were ≥50 years old; 47.6% (10/21) had received the Influenza and/or Swine Flu vaccination compared to 40.2% (33/82) in the younger age group (p=0.6). Of the 10 patients receiving dual IM and biological therapy, 9 (90%) received both annual Influenza and Swine Flu vaccinations (p
[Show abstract][Hide abstract] ABSTRACT: IntroductionCrohn's disease affecting the vulva is rarely described and often difficult to treat. The authors describe their experience of 20 patients with vulval Crohn's disease, which to their knowledge is the largest series described in the literature to date.Methods
The IBD database from 2006 to 2010 was searched for the terms ‘vulva’, ‘vulval’ and ‘Crohn's’. The case notes identified by this search were reviewed.ResultsDemographics. The median age of Crohn's disease diagnosis was 19 years (range 11–40 years). Vulval disease was the primary presentation of Crohn's disease in 2 patients. All the patients were premenopausal. The median age of vulval involvement was 27.5 years (range 19–50 years) and the median interval from Crohn's disease diagnosis to vulval disease was 9 years (range 0–32 years). 7 patients were smokers and 2 had a family history of inflammatory bowel disease. Distribution. 3 patients had metastatic disease (arising independently from other areas of Crohn's disease) while 17 had vulval involvement contiguous with perianal disease. Of the 3 patients with metastatic disease, 2 had colonic involvement and 1 ileocolonic disease distribution. Disease Severity. 11 patients had previously undergone at least 1 surgery for their Crohn's diseases. 1 patient had concomitant upper GI involvement and 3 had stricturing or penetrating disease. 4 patients had other extraintestinal manifestations (all arthropathy). Diagnosis. 5 patients were biopsied to confirm the diagnosis of vulval Crohn's. Presenting symptoms included vulval swelling (n=9), discharge (n=7), pruritus (n=1), pain (n=6), erythema (n=8), vulval ulceration (n=2) and vulval abscess (n=7). Treatment. 10 patients received antibiotics, 2 topical steroids, 12 thiopurines, 3 methotrexate, 3 topical tacrolimus and 9 biologic therapy. Of those receiving an anti-TNF treatment, 8 received Infliximab first and 1 adalimumab. 1 patient had an infusion reaction, 3 had no response. Of the 5 primary responders, 3 lost response. 1 regained response with increased frequency of Infliximab, 2 patients were switched to adalimumab.Conclusion
In this group with vulval Crohn's disease, patients predominantly had contiguous disease from perianal or rectal concurrent disease. Metastatic disease was uncommon. The majority of patients with vulval Crohn's had a severe course of their disease. Presentation was varied. There was a limited response with topical tacrolimus and 5 patients responded to anti-TNF therapy. Vulval Crohn's disease is associated with severe disease and should be suspected with patients with Crohn's disease and vulval symptoms. In keeping with previous case reports, anti-TNF therapy may be of benefit for some patients with vulval Crohn's disease.