TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs

The incidence and survival of Waldenström's Macroglobulinaemia in South East England.

Waldenström's Macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder defined as a predominately inter-trabecular bone marrow infiltration of small lymphocytes with an IgM monoclonal gammopathy. There are little reliable incidence and survival data for the disease in the UK since epidemiological studies have usually grouped it with other plasma cell dyscrasias. This study uses data from the South Thames Haematology Register and the Thames Cancer Registry for South East England to describe the incidence and survival of WM, and the influence of selected clinical factors on survival. Between 1999 and 2001, there were 152 new cases of WM recorded in the South Thames Haematology Register, giving an age standardised rate of 0.55 per 100,000 European standard population (0.73 for males and 0.42 for females). The incidence increased with age, and the median age at diagnosis was 75 years (range 45-93 years). The estimated 5 year survival was 57% (95% CI: 47-66%). Age over 70, haemoglobin less than 10 g/L and the Eastern Cooperative Oncology Group (ECOG) Performance Status grade 3-4 at diagnosis were associated with worse survival. Between 1985 and 2002, the Thames Cancer Registry recorded 750 cases of WM occurring in the wider area of South East England. The relative 5 year survival for patients aged less than 70 years was 70% (95% CI: 60-81%) and for patients aged 70 and over it was 50% (95% CI: 41-60%)

A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d (L-AMB1) or liposomal amphotericin B 3 mg/kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38°C or more, not responding to 96 h of systemic broad- spectrum antibiotic treatment, and neutropenia (< 0.5 x 10 9/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (<38°C) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P ≤ 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treated patients, in contrast to 12% of patients on c-AMB (P < 0.01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P<0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-AMB (P<0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P<0.01). Analysis was by intention-to-treat and included all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38°C) continuing to study end indicated by recovery of neutrophils to 0.5x10 9/l. Addition of systemic antifungal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB. 58% of patients responded to L- AMB1 and 64% to L-AMB3. A statistically significant difference was found between c-AMB and L-AMB3 (P= 0.03) but a Kaplan-Meier analysis of time to deffer-vescence of fever showed there was no significant difference between the arms. It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open-label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe