Precious Lacey

Optimization of human mesenchymal stem cell manufacturing: the effects of animal/xeno-free media

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-γ 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-γ primed conditions, whereas HPL-expanded MSC exhibited diminished immunosuppressive properties. Finally, IFN-γ 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.

The impact of value-based healthcare for inflammatory bowel diseases on healthcare utilization: a pilot study.

Background and objectives Value-based healthcare (VBHC) is considered to be the solution that will improve quality and decrease costs in healthcare. Many hospitals are implementing programs on the basis of this strategy, but rigorous scientific reports are still lacking. In this pilot study, we present the first-year outcomes of a VBHC program for inflammatory bowel disease (IBD) management that focuses on highly coordinated care, task differentiation of providers, and continuous home monitoring. Methods IBD patients treated within the VBHC program were identified in an administrative claims database from a commercial insurer allowing comparisons to matched controls. Only patients for whom data were available the year before and after starting the program were included. Healthcare utilization including visits, hospitalizations, laboratory and imaging tests, and medications were compared between groups. Results In total, 60 IBD patients treated at the VBHC Center were identified and were matched to 177 controls. Significantly fewer upper endoscopies were performed (−10%, P=0.012), and numerically fewer surgeries (−25%, P=0.49), hospitalizations (−28%, 0=0.71), emergency department visits (-37%, P=0.44), and imaging studies (−25 to −86%) were observed. In addition, 65% fewer patients (P=0.16) used steroids long term. IBD-related costs were 16% (

The Xenobiotic Transporter Mdr1 Enforces T Cell Homeostasis in the Presence of Intestinal Bile Acids

771) lower than expected (P=0.24). Conclusion These are the first results of a successfully implemented VBHC program for IBD. Encouraging trends toward fewer emergency department visits, hospitalizations, and long-term corticosteroid use were observed. These results will need to be confirmed in a larger sample with more follow-up.

Stem cells: HSCT for Crohn's disease: work in progress or a bridge too far?

Summary CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host‐derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild‐type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn’s disease‐like ileitis following transfer into Rag1−/− hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver‐derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1−/− mice restored Mdr1‐deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn’s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis. Graphical Abstract Figure. No caption available. HighlightsCD4+ effector T cells upregulate Mdr1 expression in the ileumMdr1 protects effector T cells in the ileum from bile‐acid‐driven oxidative stressBile acid sequestration restores Mdr1‐deficient T cell homeostasis in the ileumA subset of ileal Crohn’s disease patients display MDR1 loss of function &NA; The role of host‐derived intestinal metabolites in mucosal immune regulation is poorly understood. Here, Cao et al. show that effector CD4+ T cells upregulate expression of the xenobiotic transporter, Mdr1, in the ileum to safeguard immune homeostasis, revealing an important immunologic consequence of ileal bile acid reabsorption.

Circulating cathelicidin levels correlate with mucosal disease activity in ulcerative colitis, risk of intestinal stricture in Crohn’s disease, and clinical prognosis in inflammatory bowel disease

Haematopoietic stem cell transplantation for refractory Crohns disease has the potential to halt therapy-resistant inflammation. Hawkey et al. argue that HSCT does not offer sustained benefit based upon their recent study; however, their study was designed using suboptimal end points and patients were not offered post-transplantation Crohns disease medication.

Informatics-Based Discovery of Disease-Associated Immune Profiles.

BackgroundCathelicidin (LL-37) is an antimicrobial peptide known to be associated with various autoimmune diseases. We attempt to determine if cathelicidin can accurately reflect IBD disease activity. We hypothesize that serum cathelicidin correlates with mucosal disease activity, stricture, and clinical prognosis of IBD patients.MethodsSerum samples were collected from two separate cohorts of patients at the University of California, Los Angeles. Cohort 1 consisted of 50 control, 23 UC, and 28 CD patients. Cohort 2 consisted of 20 control, 57 UC, and 67 CD patients. LL-37 levels were determined by ELISA. Data from both cohorts were combined for calculation of accuracies in indicating mucosal disease activity, relative risks of stricture, and odds ratios of predicting disease development.ResultsSerum cathelicidin levels were inversely correlated with Partial Mayo Scores of UC patients and Harvey-Bradshaw Indices of CD patients. Among IBD patients with moderate or severe initial disease activity, the patients with high initial LL-37 levels had significantly better recovery than the patients with low initial LL-37 levels after 6–18 months, suggesting that high LL-37 levels correlate with good prognosis. Co-evaluation of LL-37 and CRP levels was more accurate than CRP alone or LL-37 alone in the correlation with Mayo Endoscopic Score of UC patients. Low LL-37 levels indicated a significantly elevated risk of intestinal stricture in CD patients.ConclusionCo-evaluation of LL-37 and CRP can indicate mucosal disease activity in UC patients. LL-37 can predict future clinical activity in IBD patients and indicate risk of intestinal stricture in CD patients.

Tu1075 The Impact of a Value-Based Health Program for Inflammatory Bowel Disease Management on Healthcare Utilization

Advances in flow and mass cytometry are enabling ultra-high resolution immune profiling in mice and humans on an unprecedented scale. However, the resulting high-content datasets challenge traditional views of cytometry data, which are both limited in scope and biased by pre-existing hypotheses. Computational solutions are now emerging (e.g., Citrus, AutoGate, SPADE) that automate cell gating or enable visualization of relative subset abundance within healthy versus diseased mice or humans. Yet these tools require significant computational fluency and fail to show quantitative relationships between discrete immune phenotypes and continuous disease variables. Here we describe a simple informatics platform that uses hierarchical clustering and nearest neighbor algorithms to associate manually gated immune phenotypes with clinical or pre-clinical disease endpoints of interest in a rapid and unbiased manner. Using this approach, we identify discrete immune profiles that correspond with either weight loss or histologic colitis in a T cell transfer model of inflammatory bowel disease (IBD), and show distinct nodes of immune dysregulation in the IBDs, Crohn’s disease and ulcerative colitis. This streamlined informatics approach for cytometry data analysis leverages publicly available software, can be applied to manually or computationally gated cytometry data, is suitable for any clinical or pre-clinical setting, and embraces ultra-high content flow and mass cytometry as a discovery engine.

Mo1837 Inhibition of microRNA-29a in Human Bone Marrow Mesenchymal Stem Cells Increases Their Immunomodulatory Function

is cardiovascular disease for which antiplatelets and anticoagulants are prescribed. Thus, baby boomers are at risk of gastrointestinal bleeding (GIB) related to both pharmacologic exposure and advancing age. In 2012, the cost of GIB care was estimated at >

The xenobiotic transporter Mdr1 permits T cell adaptation to mucosa-associated bile acids in the ileum

2.5 billion; half of which was billed to Medicare. Quantifying health care utilization of current baby boomers with GI bleeding will assist policy makers to forecast impact of this generation on future health care resource needs. Methods: A retrospective cohort study using 5 years of the Nationwide Inpatient Sample (2007-2011) was conducted to identify temporal trends in non-variceal, upperand lower-GIB to assess impact of age, co-morbidity, early vs. late endoscopy, transfer status, and disposition on the outcomes of hospital length of stay, 30day mortality and economic outcomes (charge). Temporal trends were evaluated using the Cochrane-Armitage test. The Chi-square test and multivariable linear regression models were used to quantify the impact of exposures of interest and potential effect modifiers on hospital length of stay and charge. Results: From 2007 to 2011 there were 1,322,122 hospital visits associated with GIB in 18,259,654 patients >50 years. Three-quarters of admissions were emergent, 19% occurred on the weekend and 51% were lower GIB. Overall prevalence was 7.2%, with an average length of stay (LOS) of 5.5 days (SD: 6.1) in 2007 that decreased to 5.1 days (SD: 5.7) by 2011 (p<0.001). A 1.4 day (95% CI: 1.31-1.44) increase in LOS was observed among patients ≥70 with a Charlson co-morbidity score ≥2. In-hospital mortality decreased over time from 2.5% to 2.0% (p<0.001). Total hospital charge increased over time from

P354 The effect of value based health care delivery for inflammatory bowel diseases on outcomes of patients

29,602 (2007) to