PubMed | Mayo Medical School, University of Manitoba and Center for Inflammatory Bowel Diseases
Type: | Journal: Nature reviews. Gastroenterology & hepatology | Year: 2017
Little Brain Big Brain has been a biannual meeting organized and attended exclusively by young investigators in neurogastroenterology since 1989. The XIVth meeting featured cutting-edge work advancing several novel hypotheses in the main themes of motility, inflammation and metabolism.
News Article | December 21, 2016
From established anti-inflammation agents and steroids to the latest biological drugs, people with inflammatory bowel disease (IBD) are benefiting from a growing arsenal of treatments. But the complicated network of genetic, epigenetic and environmental factors that trigger the disease is not well understood, and IBD is difficult to model in the lab. There is no cure, and for some people all therapies eventually fail. “There is still a significant minority of patients who have truly refractory, chronic active disease, and new biologics are not likely to help these patients,” says James Lindsay, who is head of the adolescent and adult IBD service at The Royal London Hospital. “These patients are in and out of hospital, they may be on intravenous nutrition, they're not working, they have morbidity from steroids and they have a truly atrocious quality of life.” Enter cell-based therapies. Among the many treatments being investigated, the furthest advanced involve the transplantation of haematopoietic stem cells, which make the body's blood cells, and treatments based on mesenchymal stem cells — adult stem cells that can differentiate into a variety of cell types. In earlier stages of investigation are efforts to construct 3D tissues called organoids using intestinal stem cells, as well as work to modify the cells that regulate the immune system. The ultimate goal of these treatments is to provide a cure for IBD. After years of study in the lab, some have reached clinical trials, although results have so far been mixed. The road to approval may well be long, but cell-based therapies offer hope to people for whom conventional treatments have failed. Found in bone marrow, haematopoietic stem cells make all of the body's blood cells, including the immune cells that overreact in IBD. For decades, people with blood cancers such as leukaemia and multiple myeloma have undergone a treatment that wipes out their haematopoietic stem cells with chemotherapy and replaces them with donated, cancer-free cells — a tough and highly toxic programme, but one that is often effective in ridding people of these cancers. Similar transplants that reboot the immune system have been shown to work in autoimmune diseases such as multiple sclerosis. In the 1990s, gastroenterologists began to notice that some people with Crohn's disease — one of the major forms of IBD — who were given transplants to treat blood cancers were also relieved of their IBD symptoms. Although these observations raised interest in cell transplants, many were concerned about the lack of evidence for a treatment that can be lethal. “There was a worry that loads of people would go through a very risky procedure, whether it was of benefit or not,” says Lindsay. That worry was the motivation behind the Autologous Stem Cell Transplantation for Crohn's Disease (ASTIC) trial, the first and so far only phase III trial designed to test the technique. Transplants in the ASTIC trial followed a similar procedure to that used for blood cancers, but instead of using cells from a donor, a patient's own stem cells were harvested and reinfused. ASTIC involved 11 centres across Europe, and enrolled 45 people with refractory Crohn's disease. In the first year, 23 volunteers were given transplants; the others received standard care (C. J. Hawkey et al. J. Am. Med. Assoc. 314, 2524–2534; 2015). Transplants were then offered to those in the control group as well. “We had two questions,” says Christopher Hawkey, ASTIC lead researcher and a gastroenterologist at the University of Nottingham, UK. “How often is Crohn's 'cured' by stem-cell transplants, and more broadly, is it effective in these people who have run out of treatment options?” The trial's main endpoint was a difficult one: sustained clinical remission after one year, which was defined as no evidence of active disease on endoscopic imaging, and patients able to stop standard medication. “It was probably unwise of me to set it like that,” says Hawkey. Such a high bar — designed to reflect the risk associated with the treatment — meant that only two people in the treatment group reached the endpoint, compared with one in the control group. As expected, the procedure resulted in many serious adverse events, including one death. Given that so few participants reached ASTIC's demanding endpoint, the researchers concluded that the trial had failed, leading some to write off these transplants for IBD. But Hawkey points out that some participants did benefit. “Half the patients had no signs of active Crohn's disease at least a year after transplant, and just over a quarter had no signs of disease all,” he says. Preliminary results from a four-year follow-up of the participants have confirmed the treatment's positive effects. “It changed people's lives,” says Lindsay, who was one of the investigators on the trial. “I had a chap who was dependent on intravenous nutrition and couldn't work. He's now off IV nutrition, he's working; he's got incomplete remission, but his life has been revolutionized.” By labelling ASTIC a failure, researchers are ignoring the potential of these transplants to help people who have exhausted the available treatments — those who cannot undergo any more surgery or cope with the toxicity of any more drugs — says Daniel Hommes, gastroenterologist and director of the Center for Inflammatory Bowel Diseases at the University of California, Los Angeles. “It definitely can be a lifesaver. The trial's very strange endpoint doesn't reflect the potency of this strategy.” Hawkey, Lindsay and other investigators have proposed a follow-up transplant trial that uses much less toxic treatment regimes. “We're not trying to kill every cancer cell in a patient,” Lindsay says. They have also suggested adopting a more modest endpoint. “If we had used the primary endpoint that the [US] Food and Drug Administration would require for a new biologic, the trial would have been very strongly positive,” he says. Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can become bone, cartilage, muscle and fat cells. They are found in bone marrow, as well as other tissues such as cord blood, dental pulp and fat. The cells have long been the subject of investigation, owing to their apparent potent ability to heal wounds without unduly alarming the immune system, says Hommes. The biggest trial success for MSCs in IBD has come in the form of local injections to help rare, but hard-to-treat, anal fistulas — a hole that is usually the result of an infection. “The MSC is a potential one-cell army to repair a fistula, to both downregulate inflammation and to regenerate the wound,” says Hommes. “And there's a lot of evidence saying that it is an effective therapy.” In a phase III randomized clinical trial of fat-derived MSCs to treat anal fistulas in those with Crohn's disease, injections of the cells resulted in the closure of fistulas in around 16% more patients than controls (J. Panés et al. Lancet 388, 1281–1290; 2016). “That's a signal to follow up on with these patients, who can be refractory to any treatment,” says one of the investigators Gert Van Assche, head of gastroenterology and hepatology at the University Hospitals Leuven, Belgium. On the basis of the results, the biotechnology firm that sponsored the trial, TiGenix in Leuven, is applying to the European Medicines Agency for approval of the treatment, which it hopes to receive in the second half of 2017. Despite this success, significant unknowns remain. “It's still largely a black box as to what was happening mechanistically inside the patient,” says Van Assche. “We can't take a biopsy, and we have to interpret results in mice with caution.” Systemic MSC treatments for IBD, which help to hit inflammation caused by the disease wherever it appears, typically elicit even greater caution from experts. Although results in mice have been tantalizing, many of the clinical trials of intravenous MSCs for IBD, and a number of other conditions, “were largely failures”, says Van Assche. “The trouble with MSCs if you administer them through a drip is that you basically count on them finding the areas of inflammation, but there's a long way for them to go,” says Hommes. “Most are lost before arriving at the site of inflammation.” Despite the lack of clinical proof, the essentially unregulated nature of stem-cell procedures in the United States means that systemic MSC treatments for conditions such as IBD are already available to patients determined to find them. For adaptive immune systems, simplicity is not a virtue. Human systems are equipped with many types of T cell. Certain regulatory T cells (T cells) that can block other inflammation-producing T cells are crucial for protecting against IBD. The Crohn's And T Cells Study (CATS1), which was sponsored by biotechnology company TxCell in Sophia Antipolis, France, examined whether activating T cells is an effective treatment for refractory Crohn's disease ( et al. Gastroenterology 143, 1207–1217; 2012). In 20 participants, T cells were isolated, primed to respond to ovalbumin — a protein that is the main component of egg whites — and reinfused. When the patients later ate a meringue cake packed with ovalbumin, their T cells were activated, which the researchers hoped would dampen the Crohn's inflammation. Six of the eight people who received a million cells showed an improvement in Crohn's symptoms at eight weeks, including two who were seemingly in remission. Encouraged by the results, the company is moving forward with a follow-up trial, which will enrol 56 patients. First results are expected in 2018. “From a basic science point of view, immune regulatory cells are very promising,” Van Assche says. “But we have to see confirming data from the larger trial.” In addition, TxCell is looking into whether T cells can be modified. The company is drawing on techniques used to engineer T cells to produce surface proteins (chimeric antigen receptors) that allow the cells to better target tumour cells in people with blood cancers. This research also benefits from recent advances in gene-editing capabilities. Re-engineering T cells could allow the specific inflammatory signals that drive IBD at an individual level to be targeted and dampened, Hommes says. But first researchers need to fully identify the specific signals involved in IBD inflammation. For example, although multiple biological drugs for IBD successfully target the protein tumour necrosis factor-α (TNF-α), “TNF-α itself has never been a distinct target for IBD”, Hommes says. It has proved to be a potent strategy, but why is unclear. Obstacles such as these keep T -cell therapy a long way from clinical use at present. “Theoretically, these treatments could be good,” says Stephan Targan at Cedars-Sinai Medical Center in Los Angeles, California, “but they're in their infancy.” Scientists have hunted for IBD treatments based on intestinal stem cells — the adult cells that keep the intestine in good repair — for the best part of a decade. Interest in these stem cells soared when, in 2009, Hans Clevers, a molecular geneticist at the Hubrecht Institute in Utrecht, the Netherlands, used the cells to build 3D tissue models called organoids. Work is at a very early stage, but organoids can now also be generated by modifying other types of cell to become induced pluripotent stem cells, which are then coaxed into becoming fully differentiated adult cells. Researchers at Cedars-Sinai Medical Center have developed intestinal organoids using stem cells derived from the cells of people with IBD, says Targan, director of the institution's Inflammatory Bowel Disease Center. When these IBD stem cells are placed in a 3D cell-culture matrix, they orient themselves and differentiate into all the cell types of the intestinal lining. Researchers can infect these organoids with bacteria or fungi, and study how the intestinal cells interact with immune cells such as macrophages derived from the same IBD cell lines. “In a year or two this technology will really make an impact,” Targan says. His ultimate goal is to use these organoids therapeutically, including as material for transplantation, “but that's a little bit down the line”, he says. David Hackam, chief of paediatric surgery at Johns Hopkins University in Baltimore, Maryland, is leading an effort to build an 'artificial intestine' with stem cells on a biodegradable scaffold. He hopes that this will eventually help to treat necrotizing enterocolitis, a rare disease among babies born prematurely in which the intestine becomes inflamed and starts to die, as well as IBD. One major hurdle was replicating the intestine's finger-like microvilli, which grab sugar, fat and protein molecules in the gut, Hackam says. To overcome this, he teamed up with John March, a biological and environmental engineer at Cornell University in Ithaca, New York, who, with his colleagues, has fabricated a scaffold with synthetic microvilli made out of collagen. “Then the trick was to take this scaffold,” says Hackam, “fold it beautifully and grow intestinal stem cells on it.” Human intestinal stem cells grew and covered the microvilli. The researchers implanted the biodegradable scaffolds in mice, where the grafts developed blood supplies ( et al. Regen. Med. 11, 45–61; 2016). The team has duplicated the feat in piglets, and is working to make the scaffold more biocompatible and more commercially viable, as well as to see whether the scaffolds can absorb nutrients. The scaffold also needs to be able to contract, because this is the process that moves the intestine's contents along. Hackam's group is studying how the organ's nerve network coordinates these contractions and how this network might be replicated from stem cells. Along with bioengineers at Johns Hopkins, the team is also pursuing a method that combines nerve cells with a device, similar to a pacemaker, that produces contractions and has a miniaturized external power supply.
Cohen B.L.,Mount Sinai School of Medicine |
Ha C.,Center for Inflammatory Bowel Diseases |
Ananthakrishnan A.N.,Harvard University |
Rieder F.,Cleveland Clinic |
Bewtra M.,University of Pennsylvania
Inflammatory Bowel Diseases | Year: 2016
Background: The fundamentals of inflammatory bowel disease (IBD) education begin during gastroenterology fellowship training. We performed a survey of gastroenterology fellowship program directors (PDs) and trainees with the aim to further examine the current state of IBD training in the United States. Methods: A 15-question PD survey and 19-question trainee survey was performed using an online platform. Results: Surveys were completed by 43/161 (27%) PDs and 160 trainees. All trainee years were equally represented. A significant proportion of trainees was unsure or believed that their inpatient (32%) or outpatient (43%) training was inadequate. Only 28% of trainees were satisfied with their current level of IBD exposure during training. Fewer than half the trainees reported comfort in the management of pouch or stoma issues, pregnant patients with IBD, or postoperative management. The proportion of PDs viewing a competency as essential for trainee education strongly correlated with trainee comfort in that area (Pearson's rho 0.793; P < 0.01). In multivariate logistic regression, monthly IBD didactics was the only variable independently associated with satisfaction with the current level of training (odds ratio, 4.1 95% CI, 1.9-9.0). Conclusions: Over one-third of participating gastroenterology trainees did not feel "confident" or "mostly comfortable" with their level of IBD training, with varying comfort regarding different competencies in IBD management. These findings suggest that specific areas of IBD training may require additional focus during training and can provide the basis for the development of an IBD core competency curriculum. © Copyright 2016 Crohn's & Colitis Foundation of America, Inc.
Zand A.,University of California at Los Angeles |
Zand A.,Center for Inflammatory Bowel Diseases |
Van Deen W.K.,University of California at Los Angeles |
Inserra E.K.,University of California at Los Angeles |
And 8 more authors.
Inflammatory Bowel Diseases | Year: 2015
Background: Indirect costs associated with impaired productivity at work (presenteeism) due to inflammatory bowel disease (IBD) are a major contributor to health expenditures. Studies estimating indirect costs in the United States did not take presenteeism into account. We aimed to quantify work limitations and presenteeism and its associated costs in an IBD population to generate recommendations to reduce presenteeism and decrease indirect costs. Methods: We performed a prospective study at a tertiary IBD center. During clinic visits, work productivity, work-related problems and adjustments, quality of life, and disease activity were assessed in patients with IBD. Work productivity and impairment were assessed in a control population as well. Indirect costs associated with lost work hours (absenteeism) and presenteeism were estimated, as well as the effect of disease activity on those costs. Results: Of the 440 included patients with IBD, 35.6% were unemployed. Significantly more presenteeism was detected in patients with IBD (62.9%) compared with controls (27.3%) (P 0.004), with no significant differences in absenteeism. Patients in remission experienced significantly more presenteeism than controls (54.7% versus 27.3%, respectively, P < 0.01), and indirect costs were significantly higher for remissive patients versus controls ($17,766 per yr versus $9179 per yr, respectively, P < 0.03). Only 34.3% had made adjustments to battle work-related problems such as fatigue, irritability, and decreased motivation. Conclusions: Patients with IBD in clinical remission still cope with significantly more presenteeism and work limitations than controls; this translates in higher indirect costs and decreased quality of life. The majority have not made any adjustments to battle these problems. © 2015 Crohn's & Colitis Foundation of America, Inc.
Mosli M.H.,Robarts Research Institute |
Mosli M.H.,King Abdulaziz University |
Macdonald J.K.,Robarts Research Institute |
Bickston S.J.,Center for Inflammatory Bowel Diseases |
And 5 more authors.
Inflammatory Bowel Diseases | Year: 2015
Background: We performed a systematic review to evaluate the efficacy and safety of vedolizumab for induction and maintenance of remission in ulcerative colitis. Methods: A literature search to June 2014 identified all applicable randomized trials. Outcome measures were clinical and endoscopic remission, clinical and endoscopic response, quality of life, and adverse events. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the quality of the evidence. Main Results: Four studies (606 patients) were included. The risk of bias was low. Pooled analyses indicated that vedolizumab was significantly superior to placebo for induction of remission (RR 0.86, 95% CI, 0.80-0.91), clinical response (RR 0.82, 95% CI, 0.75-0.91), endoscopic remission (RR 0.82, 95% CI, 0.75-0.91), and for achieving remission at 52 weeks in week 6 responders (RR 2.73, 95% CI, 1.78-4.18). GRADE analyses suggested that the overall quality of the evidence was high for induction of remission and moderate for maintenance therapy (due to sparse data consisting of 246 events). No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo. Conclusions: Vedolizumab is superior to placebo as induction and maintenance therapy for ulcerative colitis. Future studies are needed to define long-term efficacy and safety of this agent. © 2015 Crohn's & Colitis Foundation of America, Inc.
PubMed | University of California at Los Angeles and Center for Inflammatory Bowel Diseases
Type: | Journal: Scientific reports | Year: 2015
Due to their immunosuppressive properties, mesenchymal stem cells (MSC) have been evaluated for the treatment of immunological diseases. However, the animal-derived growth supplements utilized for MSC manufacturing may lead to clinical complications. Characterization of alternative media formulations is imperative for MSC therapeutic application. Human BMMSC and AdMSC were expanded in media supplemented with either human platelet lysates (HPL), serum-free media/xeno-free FDA-approved culture medium (SFM/XF), or fetal bovine serum (FBS) and the effects on their properties were investigated. The immunophenotype of resting and IFN- primed BMMSC and AdMSC remained unaltered in all media. Both HPL and SFM/XF increased the proliferation of BMMSC and AdMSC. Expansion of BMMSC and AdMSC in HPL increased their differentiation, compared to SFM/XF and FBS. Resting BMMSC and AdMSC, expanded in FBS or SFM/XF, demonstrated potent immunosuppressive properties in both non-primed and IFN- primed conditions, whereas HPL-expanded MSC exhibited diminished immunosuppressive properties. Finally, IFN- primed BMMSC and AdMSC expanded in SFM/XF and HPL expressed attenuated levels of IDO-1 compared to FBS. Herein, we provide strong evidence supporting the use of the FDA-approved SFM/XF medium, in contrast to the HPL medium, for the expansion of MSC towards therapeutic applications.