Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-ß1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-ß1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-ß1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-ßRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-ß1 than healthy control CD4+ T cells [reduced TGF-ß-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-ß1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Biomarkers in systemic sclerosis.

SSc is a CTD, which may cause critical organ fibrosis. It has a highly variable clinical presentation and course. While it is more common in females, this heterogeneity has led to significant problems with classification. Biomedical (clinical) and biomolecular markers to identify diagnostic, prognostic and therapeutic response have been elusive in part as a result of difficulties with classification and also due to the rarity of the disease. Existing biomarkers have been identified largely in small cohorts and larger cross-sectional or occasional longitudinal observational cohorts. The nature of biomarkers requires well-defined clinical characteristics and/or defined clinical outcomes and this has been extremely challenging to the international SSc research community. This brief review summarizes the current level of knowledge; however, it most importantly highlights the potential now to find biomarkers through a large, multicentre, international collaborative group approach.

Detection of myocardial infarction by immunohistological staining for C9 on formalin fixed, paraffin wax embedded sections.

AIMS: To evaluate an immunohistological stain for complement component C9 as a method of detecting early myocardial infarction and to compare this with (1) an enzyme histochemical method and (2) conventional histological staining. METHODS: (1) Eight hearts taken at necropsy were stained using the nitroblue tetrazolium/phenazine methosulphate method and an immunohistological stain for C9. (2) Twenty five hearts from cases of suspected or confirmed myocardial infarction and 25 from cases without conventional evidence of infarction were stained for C9 and by haematoxylin and eosin. RESULTS: (1) The histochemical method indicated myocardial necrosis in five hearts and the C9 method in seven, all of which had clinical evidence of myocardial damage or a reason for it. The histochemical method required fresh myocardium, was difficult to use and was difficult to interpret. (2) Of 25 hearts with suspected or confirmed infarction, 24 were stained by the C9 method. Staining with haematoxylin and eosin showed infarction in 16 of these, all with infarcts at least 24 hours old; the other eight had clinical evidence of infarction less than 24 hours old. The heart not stained by C9 was from a patient who, on review, had no evidence of infarction. Of the 25 control hearts, none had infarction on staining with haematoxylin and eosin, but three were stained by the C9 method. These three were from patients with septicaemia or another reason for myocardial damage. CONCLUSIONS: The immunohistological method for C9 is a simple, reliable and sensitive method for the detection of early myocardial necrosis that could be used on formalin fixed, paraffin wax embedded necropsy material. This had advantages over a histochemical method and conventional staining with haematoxylin and eosin.

An audit of hospital based outpatient infusions and a pilot program of community-based monoclonal antibody infusions.

INTRODUCTION: Infliximab, a chimeric monoclonal antibody to tumour necrosis factor alpha, is administered as an intravenous infusion requiring a costly hospital day case or inpatient admission. METHODS: An audit of all current therapies given by intravenous infusions in an outpatient setting in St Vincent's University Hospital (SVUH) was undertaken. Furthermore, in conjunction with TCP homecare, we established in a general practise health clinic, the first Irish community infusion centre for the administration of infliximab in August 2006. RESULTS: All outpatient departments indicated that they would favour a centralized hospital infusion unit. There were no adverse events and the mean global satisfaction improved in the community infliximab infusion pilot programme of seven patients. CONCLUSION: This study suggests efficiencies in providing centralized infusion facilities, while the community based infusion of infliximab is feasible and safe in this small cohort and identifies the community infusion unit as a viable and cost efficient alternative for administration of infliximab.

A comparison of the adhesion, coaggregation and cell-surface hydrophobicity properties of fibrillar and fimbriate strains of Streptococcus salivarius.

Fibrillar and fimbriate strains of Streptococcus salivarius were compared for their ability to adhere to buccal epithelial cells and saliva-coated hydroxyapatite beads, and for their ability to coaggregate with Veillonella strains. The fibrillar Lancefield group K strains adhered statistically significantly better to both buccal epithelial cells and saliva-coated hydroxyapatite beads than the fimbriate strains, which lacked the Lancefield group K antigen. After 1 h the fibrillar strains coaggregated statistically significantly better than the fimbriate strains with V. parvula strain V1, but after 24 h, coaggregation both of fibrillar and of fimbriate strains reached approximately 90%. Freshly isolated Veillonella strains all coaggregated with the S. salivarius strains, but the percentage coaggregation varied considerably after 1 h depending on the Veillonella strain. Coaggregation was independent of the presence of Ca2+. S. salivarius strain HB-V5, a mutant of strain HB that had lost the Veillonella-binding protein, coaggregated weakly with V. parvula strain V1, but coaggregated very well with other wild-type veillonellae, suggesting the presence of an alternative mechanism for Veillonella-binding for strain HB. Fibrillar strains were, therefore, more adhesive to oral surfaces and coaggregated with veillonellae after 1 h better than the fimbriate S. salivarius strains. Both fibrillar and fimbriate strains were highly hydrophobic in the hexadecane-buffer partition assay.