Management of postoperative recurrence of Crohn's disease

The course of Crohn's disease (CD) is unpredictable and potentially destructive. The percentage of patients requiring surgery at some stage in their disease accumulates to over 70%. After resection of the affected intestine, reappearance of CD occurs in the majority of patients. Prophylactic medical therapy to reduce the rate of postoperative recurrence has been proven to be effective, yet the incidence of recurrence remains high. Patient profiling (risk stratification) is important in this postoperative setting. High-risk patients (associated with e.g. smoking, the need of repetitive surgery and penetrating disease) require strong immunosuppressive treatment, which should be commenced immediately after surgery, when recurrent disease activity begins. Additionally, early screening endoscopy should be performed to monitor treatment effect. The efficacy of thiopurines is shown to be higher than mesalazine or imidazole antibiotics alone for preventing and ameliorating endoscopic recurrence of CD postoperatively; however, anti-tumor necrosis factors (anti-TNFs) are increasingly considered the most potent agents. In patients with a risk factor for early postoperative recurrence, the first line of treatment is 6-mercaptopurine, in combination with imidazole antibiotics if tolerated, followed by anti-TNFs. When lesions are found at colonoscopy, therapy should be upscaled. We propose a treatment algorithm to direct therapeutic management of CD postoperativel

Human thymus regeneration and T cell reconstitution

The thymus supports the development of T cells throughout life from hematopoietic progenitor cells migrating from the bone marrow. During the early years after birth thymic activity is highest, but progressively declines resulting in diminished naïve T cell output. Underlying causes of thymic involution may be degeneration of the stromal thymic network, providing survival and differentiation factors for developing T cells, or insufficiency of the progenitor cells to home and/or develop in the aged thymus. In young people the reduced thymic output is insignificant, since the peripheral T cell compartment is under compensatory homeostatic control. However, in more or less immunocompromised individuals, including aged people and patients depleted of T cells due to conditioning regimens before bone marrow transplantation or HIV infection, the thymus is necessary to replenish the peripheral T cell compartment. This may require rejuvenation of the thymus. Alternatively, approaches to generate mature T cells independent of the thymus have gained considerable interes

Thymic stromal lymphopoietin induces early human B-cell proliferation and differentiation

Thymic stromal lymphopoietin (TSLP) is a cytokine that binds the IL-7-receptor-alpha chain and a unique TSLP receptor (TSLPR) chain. The role of TSLP in human B-cell development has not been elucidated. We show that TSLPR transcripts are expressed most prominently in CD34(+) cells from fetal liver and BM. In general, cell surface expression of TSLPR was low, except on a subset of multilineage-commited progenitor cells. TSLP induced the tyrosine-phosphorylation of STAT5 and the proliferation of multilineage-commited progenitor cells, pro-B cells and pre-B cells. Compared with IL-7, the levels of proliferation after stimulation of the B-cell progenitors with TSLP were lower. Expression of the BCR on the cell surface of fetal cells was inversely correlated to TSLP or IL-7 responsiveness. Pre-B cells from fetal BM, but not fetal liver, were refractory to TSLP or IL-7 stimulation. When employing an in vitro B-cell differentiation culture system starting from CD34(+)CD38(-) multipotent HSC, IL-7 induced a short wave of precursor cell expansion but did not result in long-term survival of mature B cells. TSLP was capable of increasing the proportion and the absolute numbers of more mature human B cells. Overall, we provide evidence that TSLP supports human B-cell differentiation from fetal hematopoietic progenitor

Duration of antibiotic therapy for cholangitis after successful endoscopic drainage of the biliary tract

BACKGROUND: Drainage of the obstructed biliary tree is the mainstay of therapy for patients with acute cholangitis; antibiotic therapy is complementary. It is unknown whether it is necessary to continue therapy with antibiotics once biliary drainage is achieved and signs of systemic inflammation have subsided. METHODS: Patients who presented with acute cholangitis and were successfully treated at ERCP were studied retrospectively. Patients were followed for 6 months after ERCP. RESULTS: Eighty patients fulfilled study criteria. In 46% of patients blood cultures grew microorganisms. All patients recovered from the episode under study. Antibiotic therapy after ERCP was given for a median duration of 3 days (range: 0-42). Forty-one patients received antibiotic therapy for 3 days or less, 19 for 4 or 5 days, and 20 patients longer than 5 days. The 3 groups were well-matched. In none of the patients did the index episode of cholangitis result in a secondary complication not present at the time of ERCP. The percentage of patients with recurrent cholangitis (24%) was not statistically different for the 3 groups (p = 0.80). CONCLUSIONS: Short-duration antibiotic therapy (3 days) appears sufficient when adequate drainage is achieved and fever is abatin

Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors

In vitro production of human T cells with known Ag specificity is of major clinical interest for immunotherapy against tumors and infections. We have performed TCRalphabeta gene transfer into human hemopoietic progenitors from postnatal thymus or umbilical cord blood, and subsequently cultured these precursors on OP9 stromal cells expressing the Notch human ligand Delta-like1. We report here that fully mature, functional T cells with controlled Ag specificity are obtained from such cultures. Using vectors encoding TCRalphabeta-chains directed against melanoma (MART-1), viral (CMV), and minor histocompatibility (HA-2) Ags, we show that the obtained Ag-specific T cells exert cytolytic activity against their cognate Ag and expand in vitro upon specific TCR stimulation. Therapeutic applications may arise from these results because they provide a way to produce large numbers of autologous mature Ag-specific T cells in vitro from undifferentiated hemopoietic progenitor

In vivo modulation of gene expression by lentiviral transduction in "human immune system" Rag2-/- gamma c -/- mice

Over the last two decades, several humanized mouse models have been used to experimentally analyze the function and development of the human immune system. Recent advances have lead to the establishment of new murine-human chimeric models with improved characteristics, both in terms of human engraftment efficiency and in situ multilineage human hematopoietic development. We describe here the use of newborn BALB/c Rag2(-/-)gamma(c) (-/-) mice as recipients of human hematopoietic progenitor cells to produce "human immune system" (HIS) (BALB-Rag/gamma) mice, using human fetal liver progenitors. The two major subsets of the human dendritic cell lineage, namely, BDCA2(+)CD11c(-) plasmacytoid dendritic cells and BDCA2(-)CD11c(+) conventional dendritic cells, can be found in HIS (BALB-Rag/gamma) mice. In order to manipulate the expression of genes of interest, the human hematopoietic progenitor cells can be genetically engineered ex vivo by lentiviral transduction before performing xenograft transplantation. Using this mouse model, the human immune system can be assessed for both fundamental and pre-clinical purpose

Evaluating the endoscopic reference score for eosinophilic esophagitis: moderate to substantial intra- and interobserver reliability

Recently the Endoscopic Reference Score (EREFS) for endoscopic assessment of eosinophilic esophagitis was introduced, with good interobserver agreement for most signs. The EREFS has not yet been evaluated by other investigators and intraobserver agreement has not been assessed. The aim of this study was to further validate the EREFS by assessing interobserver and intraobserver agreement of endoscopic signs in patients with eosinophilic esophagitis. High-quality endoscopic images were made of the esophagus of 30 patients with eosinophilic esophagitis (age 36 years, range 23 - 46 years; 5 female), 6 of whom were in remission. At least three depersonalized images per patient were incorporated into a slideshow. Images were scored by four expert and four trainee endoscopists who were blinded to the patients' conditions. Interobserver agreement was assessed. After 4 weeks, the images were rescored in a different order to assess intraobserver agreement. Interobserver agreement was substantial for rings (κ 0.70), white exudates (κ 0.63), and crepe paper esophagus (κ 0.62), moderate for furrows (κ 0.49) and strictures (κ 0.54), and slight for edema (κ 0.12). Intraobserver agreement was substantial for rings (median κ 0.64, IQR 0.46 - 0.70), furrows (median κ 0.69, IQR 0.50 - 0.89), and crepe paper esophagus (median κ 0.69, IQR 0.62 - 0.83), moderate for white exudates (median κ 0.58, IQR 0.54 - 0.71) and strictures (median κ 0.54, IQR 0.33 - 0.70), and less than chance for edema (median κ 0.00, IQR 0.00 - 0.29). Inter- and intraobserver agreement was not substantially different between expert and trainee endoscopists. Using the EREFS, endoscopic signs of eosinophilic esophagitis were scored consistently by expert and trainee endoscopist