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sof anti-inflammatory M2 BMDM, determined by expression of Arg1 and Fizz1 that areclassical M2 markers, was impaired in Il10rb-/- mice. These Mϕ also expressed significantlyhigher levels of pro-inflammatory cytokines following LPS stimulation, suggesting that IL10Rsignaling regulates TLR4-dependent responses in murine anti-inflammatory Mϕ. Il10rb-/-M2 Mϕ also produced less IL10 and promoted less generation of Tregs in-vitro, perhapsdue to decreased surface expression of PD-L1 and PD-L2. Moreover, transfer of WT butnot Il10rb-/- M2 Mϕ ameliorated CD4+-induced colitis in Il10rb-/-Rag2-/- mice. Similar tomurine studies, the generation of M2 Mϕ was severely impaired in human IL10R deficientpatients. These Mϕ also secreted significantly higher levels of TNF, IL6 and IL12 followingLPS stimulation, and promoted less generation of Tregs. Conclusion: IL10R-dependentsignals play a critical role in the generation and function of blood borne and tissue residentanti-inflammatory Mϕ in mice and humans. Therapeutics and cell-based therapies aimed ataugmenting anti-inflammatory Mϕ may have clinical utility.

786

The Pharmacokinetics of Infliximab Induction Therapy in Patients WithModerate to Severe Ulcerative ColitisJohannan F. Brandse, Desiree van der Kleij, Gert-Jan Wolbink, Irma M. Rigter, Paul A.Baars, M. Lowenberg, Cyriel Ponsioen, Jeroen M. Jansen, Gijs R. van den Brink, Ron A.Mathôt, Geert R. D'Haens

Background: The mechanism behind primary non-response to infliximab (IFX) in patientswith Ulcerative Colitis (UC) is not fully understood. Although insufficient serum concentra-tions of IFX have been suggested as a cause of lack of response associated with a highinflammatory load (and hence large quantities of TNF to be neutralized), the early pharmaco-kinetics (PK) of IFX during induction therapy have been poorly studied. We studied thePK of IFX induction treatment related to inflammatory load and response in patients withmoderate and severe UC. Methods: In this multicenter prospective observational study anti-TNF Naive patients with moderate-to-severe Ulcerative Colitis (Endoscopic Mayo 2/3) startingon IFX were included after baseline endoscopy. Serum IFX concentrations, antibodies toIFX and fecal samples (IFX concentration) were collected at 10 serial time points duringthe first 6 weeks of induction therapy. Response was defined by endoscopic improvementat week 6-8. PK was analysed by nonlinear mixed-effects modelling and described using a2-compartiment PK model. Results: Fifteen UC patients were included. All but one patientreceived IFX according to the regular induction regime of 5mg/kg at week 0,2,6 and 7/15with concomitant thiopurines. 8/15 patients had no endoscopic improvement. Typical valuesand corresponding inter-patient variability (IPV) for clearance, intercompartimental clear-ance, central and peripheral volume of distribution were 0.44 L/day (IPV 26%), 0.52 L/day,3.5 L (IPV 20%) and 3.2 L (IPV 130%). Median ‘trough' level before third infusion (week6) was 2.5 ug/ml for endoscopic non-responders versus 8.2 ug/ml for responders (P=0.03).Serum IFX of ≤7ug/ml at day 42 was defined as a cut-off with OR:36 (95%CI 1.8-719, P=0.03) to predict endoscopic non-response. Four patients (1/4 used concomitant thiopurine)developed antibodies to IFX at week 6, clearance was 4.4 fold increased and peripheralvolume of distribution was 0.05 fold decreased in these patients. Fecal IFX at day 1 wassignificantly higher (P=0.02) for non-responders compared to responders. Average (± SD)post-hoc area under the IFX concentration versus time curve (AUC) was 1204 ± 507 mg/L/day 49 in the non-responders compared to 1417 ± 444 mg/L/day for the responders (p=0.42). Conclusions: A wide variation in early serum concentrations of infliximab wasobserved. Primary non-responders have lower serum concentrations at induction comparedto responders, as well as increased fecal concentrations in the first days of treatment andin some instances early development of antibodies to infliximab.

787

A High Fat Diet Containing Coconut Oil Prevents the Onset of ChronicIntestinal Inflammation in Experimental Crohn's DiseaseAshley Trotter, Alexander Rodriguez-Palacios, Lindsey Kaydo, Davide Pietropaoli, WeiXin, Colleen M. Croniger, Fabio Cominelli

Background & Aims: Consumption of a high fat diet has been shown to increase the severityof colonic inflammation and alter the commensal flora in mouse models of colitis. In addition,obesity has been associated with increased disease severity in patients with IBD. However,the effects of high fat intake on small intestinal inflammation have not been fully elucidated.In this study we tested the effects of a high fat diet containing coconut oil (medium chainfatty acids) in SAMP1/YitFc (SAMP) mice with CD-like ileitis. Methods: SAMP mice werefed a high-fat diet (H) (kcal-16% protein, 58% saturated fat-coconut oil, 26% carbohydrate,0 ppm choline) or a standard rodent diet (N) for 24 wks starting at 6 wks of age. AKRcontrol mice were fed the same H and N diets. Body weight and glucose levels were monitored

S-134AGA Abstracts

weekly and monthly, respectively. Ilea were directly examined using a stereomicroscopictechnique to calculate the percentages of abnormal mucosa. Ileal total inflammatory scores(based on histologic indices of chronic, active, and villous distortion) were determined atthe time of sacrifice (30 wks). Intestinal permeability was assessed using the FITC-dextrantechnique. In a separate experiment, germ-free (GF) SAMP with spontaneous colitis (n=9)were transplanted with fecal matter from either 26-wk-old SAMP H or SAMP N; controlGF SAMP received only PBS (n=6 for all groups). After 3d, mice were sacrificed and colontissues examined for severity of colitis by MPO assay. Results: Body weight markedly increasedin AKR H (n=12) compared to AKR N (n=10) by 40%. By comparison, SAMP H (n=12)also gained more weight vs SAMP N (n=12) by 55%. However, weight gain in SAMP H at30 wks was significantly lower than AKR H (-44%) and comparable to that of AKR N(p<0.001). No significant differences were observed in glucose levels among groups. Evalua-tion of ilea by stereomicroscopy demonstrated that SAMP H had markedly lower percentagesof abnormal gut mucosa (8.7±3.0 vs 40.1±5.2, n=4; p<0.05), and histologically exhibitedlower total inflammatory scores (0.8±0.1 vs 6.3±0.3, n=11; p<0.001) compared to SAMPN. Interestingly, 7/11 SAMP H mice showed complete prevention of ileitis (p<0.004). Nosignificant differences in intestinal permeability were observed between SAMP H and SAMPN. Fecal transplantation from SAMP H donors suppressed colonic MPO activity in SAMPGF mice compared to SAMP N donors or controls (p<0.05). Conclusions: Our study demon-strates that a high fat diet containing coconut oil prevented the onset of ileitis in SAMPmice. These effects appear to be mediated by induction of a "tolerogenic" commensal flora.We conclude that dietary administration of medium chain saturated fatty acids has a signifi-cant anti-inflammatory effect in spontaneous CD-like ileitis, without inducing metabolic orweight abnormalities.

788

Higher 6-Thioguanine Nucleotide Concentrations Are Associated With HigherTrough Levels of Infliximab in Patients on Combination TherapyAndres Yarur, Maddie Kubiliun, Katherine Drake, Scott Hauenstein, Jamie S. Barkin,Daniel A. Sussman, Amar R. Deshpande, Maria A. Quintero, Sharat Singh, Maria T. Abreu

BACKGROUND The treatment of inflammatory bowel diseases (IBD) includes drugs suchas infliximab (IFX) and thiopurines. The combination of both drugs has been shown to bemore effective than monotherapy through several mechanisms including higher anti-TNFlevels and decreased immunogenicity against the drug. 6-thioguanine (6TGN) is a thiopurinemetabolite and higher levels are linked with better clinical outcomes. The aim of this studywas to assess if there is a correlation between 6TGN and IFX levels and antibodies toinfliximab (ATI). METHODS This was a cross-sectional study of IBD patients receivingmaintenance therapy with IFX in combination with a thiopurine (azathioprine or 6-mercapto-purine) for ≥4 months and in whom levels of both were measured within 2 weeks of eachdraw. Predictive variables included demographics, IBD phenotype, laboratories (includinga complete blood count and C-reactive protein), the dose of thiopurine the patient wastaking and metabolites levels (6-TGN and 6-methylmercaptopurine [6-MMP]). The primaryoutcome was the IFX through level and the presence of ATI measured using a mobility shiftassay, which allows the detection of ATI in the presence of IFX (Prometheus labs, San Diego,CA). Spearman's rho was used to correlate levels. Quartile analysis and receiving operatingcurves (ROC) were performed to identify the best cutoff 6TGN concentration that predictedhigher anti-TNF levels. RESULTS 72 patients were included. The baseline characteristicsare shown in Table 1. There was a significant positive correlation between 6TGN levels andIFX levels (rho: 0.477 [p<0.0001]) but there was no correlation between thiopurine doseor lymphocyte count and IFX level (rho: -0.05 [p=0.71] and rho: 0.12 [p=0.3] respectively).A 6TGN level ≥ 125 pmol/8X108 RBC best predicted higher anti-TNF levels (ROC: 0.82,p=0.002). There was a positive correlation between 6TGN and 6MMP levels (rho: 0.42,p<0.001) and a negative correlation between 6TGN and lymphocyte count (rho: -0.36, p=0.002). While there was a correlation between 6MMP concentrations and IFX levels, in themultiple regression analysis, only 6TGN level was predictive of IFX measurements (p<0.001).Only 8 patients had detectable ATI (11%); the differences between groups with and withoutATI are shown in Table 2. Those patients with 6TGN levels <125 pmol/8X108 had a higherchance of having detectable ATI (OR: 1.3 [95%CI 2.3-72.5, p<0.01]). CONCLUSIONS 6-TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizingtreatment when using thiopurines in combination with IFX. Therapeutic levels of 6-TGN(>232) were not necessary to achieve higher trough levels of IFX. Thus, in patients oncombination therapy, lower target 6TGN levels (125 pmol/8X108 RBC) may maximize IFXlevels while minimizing toxicity.Table 1: Baseline characteristics of the study population