AGA Abstracts

of anti-inflammatory M2 BMDM, determined by expression of Arg1 and Fizz1 that are

classical M2 markers, was impaired in Il10rb-/- mice. These M also expressed significantly
higher levels of pro-inflammatory cytokines following LPS stimulation, suggesting that IL10R
signaling regulates TLR4-dependent responses in murine anti-inflammatory M. Il10rb-/M2 M also produced less IL10 and promoted less generation of Tregs in-vitro, perhaps
due to decreased surface expression of PD-L1 and PD-L2. Moreover, transfer of WT but
not Il10rb-/- M2 M ameliorated CD4+-induced colitis in Il10rb-/-Rag2-/- mice. Similar to
murine studies, the generation of M2 M was severely impaired in human IL10R deficient
patients. These M also secreted significantly higher levels of TNF, IL6 and IL12 following
LPS stimulation, and promoted less generation of Tregs. Conclusion: IL10R-dependent
signals play a critical role in the generation and function of blood borne and tissue resident
anti-inflammatory M in mice and humans. Therapeutics and cell-based therapies aimed at
augmenting anti-inflammatory M may have clinical utility.

weekly and monthly, respectively. Ilea were directly examined using a stereomicroscopic
technique to calculate the percentages of abnormal mucosa. Ileal total inflammatory scores
(based on histologic indices of chronic, active, and villous distortion) were determined at
the time of sacrifice (30 wks). Intestinal permeability was assessed using the FITC-dextran
technique. 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; control
GF SAMP received only PBS (n=6 for all groups). After 3d, mice were sacrificed and colon
tissues examined for severity of colitis by MPO assay. Results: Body weight markedly increased
in 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 at
30 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. Evaluation of ilea by stereomicroscopy demonstrated that SAMP H had markedly lower percentages
of abnormal gut mucosa (8.73.0 vs 40.15.2, n=4; p<0.05), and histologically exhibited
lower total inflammatory scores (0.80.1 vs 6.30.3, n=11; p<0.001) compared to SAMP
N. Interestingly, 7/11 SAMP H mice showed complete prevention of ileitis (p<0.004). No
significant differences in intestinal permeability were observed between SAMP H and SAMP
N. Fecal transplantation from SAMP H donors suppressed colonic MPO activity in SAMP
GF mice compared to SAMP N donors or controls (p<0.05). Conclusions: Our study demonstrates that a high fat diet containing coconut oil prevented the onset of ileitis in SAMP
mice. 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 significant anti-inflammatory effect in spontaneous CD-like ileitis, without inducing metabolic or
weight abnormalities.

786
The Pharmacokinetics of Infliximab Induction Therapy in Patients With
Moderate to Severe Ulcerative Colitis
Johannan 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.
Matht, Geert R. D'Haens
Background: The mechanism behind primary non-response to infliximab (IFX) in patients
with Ulcerative Colitis (UC) is not fully understood. Although insufficient serum concentrations of IFX have been suggested as a cause of lack of response associated with a high
inflammatory load (and hence large quantities of TNF to be neutralized), the early pharmacokinetics (PK) of IFX during induction therapy have been poorly studied. We studied the
PK of IFX induction treatment related to inflammatory load and response in patients with
moderate and severe UC. Methods: In this multicenter prospective observational study antiTNF Naive patients with moderate-to-severe Ulcerative Colitis (Endoscopic Mayo 2/3) starting
on IFX were included after baseline endoscopy. Serum IFX concentrations, antibodies to
IFX and fecal samples (IFX concentration) were collected at 10 serial time points during
the first 6 weeks of induction therapy. Response was defined by endoscopic improvement
at week 6-8. PK was analysed by nonlinear mixed-effects modelling and described using a
2-compartiment PK model. Results: Fifteen UC patients were included. All but one patient
received IFX according to the regular induction regime of 5mg/kg at week 0,2,6 and 7/15
with concomitant thiopurines. 8/15 patients had no endoscopic improvement. Typical values
and corresponding inter-patient variability (IPV) for clearance, intercompartimental clearance, 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 (week
6) 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 peripheral
volume of distribution was 0.05 fold decreased in these patients. Fecal IFX at day 1 was
significantly 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 was
observed. Primary non-responders have lower serum concentrations at induction compared
to responders, as well as increased fecal concentrations in the first days of treatment and
in some instances early development of antibodies to infliximab.

788
Higher 6-Thioguanine Nucleotide Concentrations Are Associated With Higher
Trough Levels of Infliximab in Patients on Combination Therapy
Andres 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 such
as infliximab (IFX) and thiopurines. The combination of both drugs has been shown to be
more effective than monotherapy through several mechanisms including higher anti-TNF
levels and decreased immunogenicity against the drug. 6-thioguanine (6TGN) is a thiopurine
metabolite and higher levels are linked with better clinical outcomes. The aim of this study
was to assess if there is a correlation between 6TGN and IFX levels and antibodies to
infliximab (ATI). METHODS This was a cross-sectional study of IBD patients receiving
maintenance therapy with IFX in combination with a thiopurine (azathioprine or 6-mercaptopurine) for 4 months and in whom levels of both were measured within 2 weeks of each
draw. Predictive variables included demographics, IBD phenotype, laboratories (including
a complete blood count and C-reactive protein), the dose of thiopurine the patient was
taking and metabolites levels (6-TGN and 6-methylmercaptopurine [6-MMP]). The primary
outcome was the IFX through level and the presence of ATI measured using a mobility shift
assay, 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 operating
curves (ROC) were performed to identify the best cutoff 6TGN concentration that predicted
higher anti-TNF levels. RESULTS 72 patients were included. The baseline characteristics
are shown in Table 1. There was a significant positive correlation between 6TGN levels and
IFX levels (rho: 0.477 [p<0.0001]) but there was no correlation between thiopurine dose
or 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 the
multiple 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 without
ATI are shown in Table 2. Those patients with 6TGN levels <125 pmol/8X108 had a higher
chance of having detectable ATI (OR: 1.3 [95%CI 2.3-72.5, p<0.01]). CONCLUSIONS 6TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizing
treatment 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 on
combination therapy, lower target 6TGN levels (125 pmol/8X108 RBC) may maximize IFX
levels while minimizing toxicity.
Table 1: Baseline characteristics of the study population

787
A High Fat Diet Containing Coconut Oil Prevents the Onset of Chronic
Intestinal Inflammation in Experimental Crohn's Disease
Ashley Trotter, Alexander Rodriguez-Palacios, Lindsey Kaydo, Davide Pietropaoli, Wei
Xin, Colleen M. Croniger, Fabio Cominelli
Background & Aims: Consumption of a high fat diet has been shown to increase the severity
of 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 chain
fatty acids) in SAMP1/YitFc (SAMP) mice with CD-like ileitis. Methods: SAMP mice were
fed 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. AKR
control mice were fed the same H and N diets. Body weight and glucose levels were monitored

AGA Abstracts

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