Stem cell therapy for inflammatory bowel disease

Hematopoietic stem cell transplantation (HSCT) and mesenchymal stromal (MSC) cell therapy are currently under investigation as novel therapies for inflammatory bowel diseases (IBD). Hematopoietic stem cells are thought to repopulate the immune system and reset the immunological response to luminal antigens. MSCs have the capacity to differentiate into a wide variety of distinct cell lineages and to suppress immune responses in vitro and in vivo. The main goal of this thesis was to study the safety, feasibility, and applicability of stem cell therapy in IBD. Chapter 2 concludes that autologous HSCT appears to be safe and can be an alternative strategy for Crohn__s disease patients with severe and therapy resistant disease. Data from the phase I study described in Chapter 3 demonstrates that MSCs isolated from Crohn__s disease patients have similar characteristics compared to MSCs from healthy donors and that administration of autologous bone marrow derived MSCs appears to be safe and feasible in the treatment of refractory Crohn__s disease. Chapter 4 shows that MSC phenotype and function are not affected by therapeutic concentrations of drugs commonly used in the treatment of IBD. Chapter 5 demonstrates that IFN-_ activation of MSCs increases their immunosuppresive capacities and importantly, their therapeutic efficacy in vivo.Financial support for the publication of this thesis was kindly provided by ABBOTT Immunology, Bayer HealthCare Pharmaceuticals, ChipSoft B.V., Dr. Falk Pharma Benelux B.V. Dutch Digestive Foundation (Maag Lever Darm Stichting), EuroTec B.V., J.E. Jurriaanse Stichting, Ferring B.V. Merck Sharp & Dohme B.V, Netherlands Society of Gastroenterology (NVGE), Olympus Nederland B.V. Section Experimental Gastroenterology (SEG) of the Netherlands Society of Gastroenterology (NVGE), Tramedico B.V.UBL - phd migration 201

Prognostic Value of Colonic Tissue and Blood Eosinophils in Ulcerative Colitis.

BACKGROUND It has been suggested that eosinophils may be a prognostic marker of disease outcome in ulcerative colitis (UC), but conflicting data exist. The objective was to investigate the extent of mucosal eosinophils and peripheral blood eosinophil count in newly diagnosed UC patients and to investigate its predictive value in short- and long-term disease outcomes. METHODS The degree of eosinophilia in baseline colonic biopsies and blood of newly diagnosed UC patients was retrospectively analyzed. It was investigated if tissue and blood eosinophilia could be a marker of a severe phenotype of UC, defined as the need for corticosteroids or immunomodulators in the first year or treatment with therapeutic monoclonal antibodies or colectomy during follow-up. Time to therapeutic monoclonal antibodies and time to colectomy were also evaluated as outcomes. RESULTS There were 103 UC patients (median age 26 years) included. Median tissue peak eosinophil count (PEC) was 70.0 and median peripheral blood eosinophil count was 0.3 × 109/L at diagnosis. Tissue PEC (r = -0.161, P = .104) and blood eosinophil count (r = 0.022, P = .877) were not correlated with the severity of histologic inflammation. Logistic regression analyses did not identify PEC and blood eosinophil count as predictors of more severe disease outcomes. Tissue PEC and peripheral blood eosinophil count did not predict the time the initiation of therapeutic monoclonal antibodies or colectomy. CONCLUSION Baseline tissue or peripheral blood eosinophils are not markers of disease activity and cannot be used as a predictor of severe disease outcomes in both adults and children with UC

The influence of different floor-surf ace on starting to move a wheelchair

高齢者用車いすが在宅床面素材によってどのような影響を受けるのかを調べるため、特性の異なる車いす7台を用い、6種の床面で始動力を測定した。その結果、床面の種類、車いすの種類に有意な差を認めたため、さらに各床面で最も軽く、または重くなる車いすの構成要因を分析した。フローリンクとパイルカーペットでは、主輪空気圧を高めたものが軽く(p<0.01)なった。畳ではエアーキャスター付き車いすが軽く(p<0.01)、ソリットキャスターと主輪の空気圧を高めたものが最も重く(p<0.01)なった。畳にカーベットを敷いた床面では、ソリットキャスターと主輪の空気圧を高めたものが最も重く(p<0.01)なった。敷居や戸当段差では、81～252Nと他の床面に比べて全ての車いすが重く(p<0.01)なったが、その中でもエアーキャスターを装備する車いすは軽く(p<0.01)なった。このことから、床面の違いによって車いすの始動力は大きく影響を受け、硬い床面で軽く、柔らかな床面で始動力は重くなり、病院や施設で軽く動く車いすが在宅では同じ特性とならないことが明確となった。使用環境により車いすの構造や部品選択基準が異なることが示唆された。今回の研究により、住環境の床面条件に合わせた車いす構成要素の選択が重要であると考えられた。 / This study was conducted in order to examine the influence of different floor-surfaces on starting to move a wheelchair. The measurement performed in this study was the force required to move a wheelchair under six conditions of floor-surface, using seven types of wheelchair. Analysis of variance (ANOVA) was done among the different conditions and different types of wheelchair. As a result, significant differences were found depending on the conditions of floor-surfaces and the types of wheelchair. Therefore, we analyzed the composition factor of the wheelchair for which the force to move is the lowest, or the highest, on each floor-surface. ANOVA revealed, on flooring and pile carpet, the force to move a wheelchair with high pressure in its main tires was the lowest (p<0.01). On a tatami mat, that of the wheelchair with air casters was the lowest (p<0.01), while that of the wheelchair with solid casters and the one with high-pressure main tires was the highest (p<0.0l). On a carpeted tatami mat, that of the wheelchair with solid casters and the one with high-pressure main tires was also the highest (p<0.0l). At threshold and doorsill, the force was high (81-252N) compared with the other floor-surfaces and all wheelchairs, although that of the wheelchair with air casters was lower than others (p<0. 01). The differences of floor-surface have a great influence on the force required to move a wheelchair; it is higher on soft floor-surfaces and lower on hard floor-surfaces. It became obvious that wheelchairs which move easily at hospitals and facilities did not show the same characteristic at the home. The results of this study suggest that the structure and choice of parts for a wheelchair should be considered in relation to the environment where it will be used, with particular attention to floor-surface materials

Miltefosine Suppresses Inflammation in a Mouse Model of Inflammatory Bowel Disease

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Ustekinumab trough concentrations are associated with biochemical outcomes in patients with Crohn's disease

Objective: It is unknown whether ustekinumab (UST) levels can predict clinical outcomes in Crohn's disease (CD) patients. We assessed the exposure-response relationship of UST trough concentrations with biochemical outcomes at week 24 in a prospective, real-world setting. Methods: We performed a prospective study in patients with CD starting UST in four academic centres in the Netherlands. All patients received a weight-adjusted intravenous (IV) UST induction dose, followed by one subcutaneous (SC) dose of 90 mg UST at 8 weeks. Maintenance therapy consisted of 90 mg subcutaneous UST every 8 or 12 weeks. Individual UST concentration time course during treatment were estimated using a population pharmacokinetic (PK) model. Quartile analysis and logistic regression were performed to analyse if UST concentrations at week 8 were associated with biochemical remission rates at week 24 (C-reactive protein (CRP) = 6.3 mu g/mL at week 8) had higher biochemical remission rates at week 12 and week 24. There was no association between UST levels at and corticosteroid-free clinical remission rates .Conclusion: In this real-world cohort of patients with CD, UST levels in the highest quartile (>= 6.3 mu g/mL) at week 8 were associated with higher biochemical remission rates at week 24.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review

SummaryBackgroundAn important goal of stem cell research in orthopaedics is to develop clinically relevant techniques that could be applied to heal cartilage or joint pathology. Stem cell treatment in orthopaedics for joint pathology is promising since these cells have the ability to modulate different processes in the various tissues of the joint simultaneously. The non life-threatening nature of musculoskeletal system disorders makes safety of stem cell therapy a necessary prerequisite.ObjectiveTo systematically review the literature and provide an overview of reported adverse events (AEs) of intra-articular treatment with culture-expanded stem cells in humans.DesignA systematic literature search was performed in Pubmed, EMBASE, Web of Science and CINAHL in February 2013. AEs were reported into three categories: local/systemic, serious adverse event or AE (SAE/AE), related/unrelated.Results3039 Potentially eligible articles were identified of which eventually eight fulfilled our inclusion criteria. In total, 844 procedures with a mean follow-up of 21 months were analysed. Autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) were used for cartilage repair and osteoarthritis treatment in all included studies. Four SAEs were reported by the authors. One infection following bone marrow aspiration (BMA) was reported as probably related and resolved with antibiotics. One pulmonary embolism occurred 2 weeks after BMA and was reported as possibly related. Two tumours, both not at the site of injection, were reported as unrelated. Twenty-two other cases of possible procedure-related and seven of possible stem cell-product related adverse events (AEs) were documented. The main AEs related to the procedure were increased pain/swelling and dehydration after BMA. Increased pain and swelling was the only AE reported as related to the stem cell-product.ConclusionsBased on current literature review we conclude that application of cultured stem cells in joints appears to be safe. We believe that with continuous caution for potential side effects, it is reasonable to continue with the development of articular stem cell therapies

Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system

Effectiveness and safety of tofacitinib for ulcerative colitis: two-year results of the ICC Registry

Background Tofacitinib is an oral Janus kinase (JAK) inhibitor and is registered for the treatment of ulcerative colitis (UC). The effectiveness of tofacitinib has been evaluated up to 12 months of treatment. Aim The aim of this study was to assess the effectiveness and safety of 24 months of tofacitinib use in UC patients in the Netherlands. Methods Patients initiating tofacitinib treatment were included in the ICC Registry, a nationwide, observational registry. Patients were prospectively evaluated for up to 24 months. The primary outcome was corticosteroid-free clinical remission (CSFR, Simple Clinical Colitis Activity Index [SCCAI] <= 2) at week 104. Secondary outcomes included biochemical remission (C-reactive protein (CRP) <= 5 mg/L and faecal calprotectin (FC) <= 250 mu g/g), safety, and discontinuation rate. Results We included 110 patients of whom 104 (94.5%) were anti-TNF experienced. After 104 weeks of tofacitinib, 31.8% (34/107) were in CSFR, 23.4% (25/107) in biochemical remission and 18.7% (20/107) in combined clinical and biochemical remission. Of the patients in CSFR at week 52, 76.5% (26/34) remained so after 104 weeks of treatment. Sixty-one patients (55.5%) discontinued tofacitinib after a median duration of 13 weeks (IQR 7-34). The main reasons for discontinuation were non-response (59%), loss of response (14.8%), and adverse events (18%). There were 33.9 possible tofacitinib-related adverse events per 100 patient-years during follow-up. Adverse events most probably related to tofacitinib were skin reactions and headaches. There were 6.4 herpes zoster infections per 100 patient-years. Conclusion Tofacitinib was effective in 31.8% of patients after 24 months of treatment.Cellular mechanisms in basic and clinical gastroenterology and hepatolog