Arne Koscielny

T helper type 1 memory cells disseminate postoperative ileus over the entire intestinal tract

Localized abdominal surgery can lead to disruption of motility in the entire gastrointestinal tract (postoperative ileus). Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how the macrophages are activated, especially those in unmanipulated intestinal areas. Here we show that intestinal surgery activates intestinal CD103+CD11b+ dendritic cells (DCs) to produce interleukin-12 (IL-12). This promotes interferon-γ (IFN-γ) secretion by CCR9+ memory T helper type 1 (TH1) cells which activates the macrophages. IL-12 also caused some TH1 cells to migrate from surgically manipulated sites through the bloodstream to unmanipulated intestinal areas where they induced ileus. Preventing T cell migration with the drug FTY720 or inhibition of IL-12, T-bet (TH1-specific T box transcription factor) or IFN-γ prevented postoperative ileus. CCR9+ TH1 memory cells were detected in the venous blood of subjects 1 h after abdominal surgery. These findings indicate that postoperative ileus is a TH1 immune-mediated disease and identify potential targets for disease monitoring and therapy.

Simultaneous MR arteriography and venography with blood pool contrast agent detects deep venous thrombosis in suspected arterial disease.

OBJECTIVE The purpose of this study was to investigate the prevalence of incidental deep venous thrombosis (DVT) in patients with clinically suspected peripheral arterial occlusive disease (PAOD) using contrast-enhanced MR angiography (MRA) with a blood pool contrast agent. SUBJECTS AND METHODS Two hundred fifty-nine MRA examinations with blood pool contrast agent in 245 consecutive patients (161 men; age range, 36-92 years), yielding a total of 4102 assessable arterial and venous vessel segments, were assessed with regard to the rate of incidentally observed acute and organized DVT and arterial stenosis grades. Incidental DVT was confirmed using duplex ultrasound. Contralateral nondiseased veins served as internal controls. The relationship between PAOD stages and acute and organized DVT was investigated using chi-square tests and a Mann-Whitney U test. RESULTS Arterial stenosis grading using MRA with blood pool contrast agent revealed less than 50% luminal stenosis in 78% of segments (3199/4102), 50% or greater stenosis in 8% of segments (317/4102), and occlusion in 14% of segments (586/4102). Incidental DVT was observed in 26 of 245 patients (11%) (acute DVT was seen in 10 patients and 26 segments; organized DVT was seen in 17 patients and 35 segments; and one patient had both acute and organized DVT). All incidentally diagnosed cases of DVT were confirmed by duplex ultrasound. Internal controls revealed no false-positive or -negative findings (26 patients and 172 segments). Incidental acute DVT was significantly more common among patients without arterial stenosis greater than 50% (p < 0.05). Otherwise, there was no significant relationship between Fontaine PAOD stages and the occurrence of acute (p = 0.688) or organized (p = 0.995) DVT. CONCLUSION Incidental DVT was prevalent in 11% of patients with clinically suspected PAOD. MRA with blood pool contrast agent has a potential role in the simultaneous assessment of arteries and veins and can detect concomitant venous disease affecting therapeutic management.

Acute rejection and the muscularis propria after intestinal transplantation: the alloresponse, inflammation, and smooth muscle function.

Background. It has been shown that in transplantation the intestinal muscularis may act as an immunologically active layer via the activation of resident macrophages and the recruitment of leukocytes. Thus we hypothesized that inflammation within the intestinal muscularis is involved in the promotion of acute rejection in intestinal allografts and that this causes smooth muscle dysfunction. Methods. Orthotopic allogenic and small bowel transplantation (Brown-Norway rats–Lewis rats) was performed without immunosuppression. Animals were sacrificed 1, 4, and 7 days after small bowel transplantation. Isogenic transplanted grafts (Brown-Norway rats–Brown-Norway rats) as well as nontransplanted bowel served as controls. Mediator mRNA expression was determined by real-time reverse-transcriptase polymerase chain reaction. Leukocyte infiltration was evaluated in muscularis whole mounts by immunohistochemistry. Apoptosis was evaluated by TdT-mediated dUTP-X nick end labeling assay. Contractility was assessed in a standard organ bath under bethanechol stimulation. Statistical analysis was performed using a Student’s t test and one-way analysis of variance. Results. Transplanted animals showed a significant early inflammatory response within the graft muscularis because of reperfusion injury. Only allogenic transplanted animals exhibited a significant second molecular inflammatory peak in the muscularis during rejection (mRNA induction for interleukin (IL)-6, intercellular adhesion molecule-1, monocyte chemoattractant protein (MCP)-1, interferon-&ggr;, IL-2, tumor necrosis factor-&agr;, IL-10, inducible nitric oxide synthase). These findings were associated with significant leukocyte infiltration within the muscularis, increasing apoptotic cells and massive impairment of smooth muscle contractile activity by 78%. Conclusions. The data shows that transplantation results in an early and temporary inflammatory response within the intestinal graft muscularis, that is reactivated and intensified during acute allograft rejection. The immunoreaction within the intestinal muscularis leads to intestinal allograft smooth muscle dysfunction.

Magnetic resonance (MR) imaging and MR angiography for evaluation and follow-up of hepatic artery banding in patients with hepatic involvement of hereditary hemorrhagic telangiectasia

BackgroundWe describe findings obtained by magnetic resonance angiography (MRA) and magnetic resonance imaging (MRI) for evaluation and follow-up after hepatic artery banding in patients with hepatic involvement of hereditary hemorrhagic telangiectasia (HHT).MethodsAbdominal MRA and liver MRI were performed in three patients with HHT as clinically defined by Curacao criteria. One patient underwent MRA and MRI twice for preinterventional evaluation and follow-up, one patient for preinterventional evaluation, and one patient for postinterventional evaluation. Hepatic vascular involvement of the disease and postinterventional vascular anatomy were evaluated by two radiologists by consensus.ResultsHepatic vascular involvement with perfusion disorders and arteriosystemic shunts was found in all three patients. MRA and MRI allowed diagnostic characterization of hepatic vascular disease (three of three), preinterventional evaluation of complex vascular anatomy and variants (two of two), and postinterventional follow-up of hepatic artery banding (two of two).ConclusionIn preinterventional evaluation and postinterventional follow-up, MRA and MRI allows characterization of complex hepatic vascular alterations of HHT and, hence, is an alternative to other imaging modalities in the diagnosis, clinical decision making, and follow-up of HHT.

The role of lymphoid tissue in the attenuation of the postoperative ileus

Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune-mediated. The aim of this study was to investigate the role of secondary lymphoid organs [mesenteric lymph nodes (MLN), gut-associated lymphoid tissue (GALT)] in IM-mediated FE by employing mice with deficient secondary lymphoid organs (aly/aly, MLN ex) or by administration of 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol (FTY720), an immunomodulating agent that inhibits emigration of lymphocytes out of lymphoid organs. Small bowel muscularis, and colonic muscularis from wild-type mice as control, from aly/aly mice, FTY720-treated mice (daily dose of 1.0 mg/kg mouse ip starting 3 days before surgical procedure), and wild-type mice that had undergone removal of mesenteric lymph nodes before IM (MLN ex mice) were obtained after selective IM of the jejunum or sham operation. FE was analyzed by measuring transit time of orally administered fluorescent dextran in the gastrointestinal tract [geometric center (GC) of fluorescent dextran], colonic transit time, infiltration of myeloperoxidase-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1α] were determined by Taqman-PCR. We observed a significantly reduced upregulation of proinflammatory cytokines (IL-6, TNF-α, MIP-1α) in colonic muscularis of MLN ex mice, aly/aly mice, and FTY720-treated mice compared with wild-type mice. Contractility of circular muscularis strips of the colon but not the jejunum was significantly improved in aly/aly mice and FTY720-treated wild-type mice. Additionally, inflammation of the colon determined by the number of myeloperoxidase-positive cells and colonic transit time were significantly improved in aly/aly mice, FTY720-treated wild-type mice, and in MLN ex mice. In summary, lack of secondary lymphoid organs (MLN + GALT) in aly/aly mice or administration of FTY720 abrogated FE after IM as opposed to wild-type mice. These data demonstrate that secondary lymphoid organs are involved in the propagation of FE and postoperative ileus. FTY720 indirectly affects FE by inhibiting migration of activated T cells from the jejunum and adjacent secondary lymphoid organs to the colon. These findings support the crucial role of the adaptive immune system in FE, most likely by a sphyngosine 1-phosphate-dependent mechanism.

T-helper cell type 1 memory cells and postoperative ileus in the entire gut.

Purpose of review The pathophysiological riddle of the clinically important postoperative ileus (POI) has been solved more and more over the last decade. The POI is caused by inflammation and paralysis at the manipulated site propagating to the entire, unmanipulated gastrointestinal tract. Intestinal macrophages produce mediators that paralyze myocytes, but it is unclear how macrophages are activated, particularly those in unmanipulated areas. In addition to direct or neurally mediated activation of intestinal macrophages, a new immunologically mediated activation has been proposed. Recent findings Recently, it has been shown that the surgical trauma induces interleukin-12 (IL-12) production by intestinal dendritic cells, which activates TH1-memory cells at the manipulated site. Those TH1-memory cells produce interferon-&ggr; (IFN-&ggr;). Those TH1 CCR9+ cells also migrate to unmanipulated parts of the gastrointestinal tract. Their IFN-&ggr; stimulates intestinal macrophages to produce nitirc oxide paralyzing myocytes leading to gastrointestinal hypomotility. Summary The involvement of the adaptive (T-helper type 1 cell-mediated immune response) and of the innate (mast cells, intestinal macrophages) immune system in the pathophysiology of POI displays possible targets for objective monitoring and treatment of POI.

Highly undersampled supraaortic MRA at 3.0 T: initial results with parallel imaging in two directions using a 16-channel neurovascular coil and parallel imaging factors up to 16

PURPOSE To present the feasibility of highly undersampled contrast-enhanced MRA (CE-MRA) of the supraaortic arteries with a 16-channel neurovascular coil at 3.0 T using parallel imaging in two directions with parallel imaging factors (PIF) up to 16. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. In a prospective study, MRA protocols including PIF of 1, 2, 4, 9 and 16 yielding a spatial resolution from 0.81×0.81×1.0 mm(3) to 0.46×.46×0.98 mm(3) were acquired. In 32 examinations, image quality and vascular segments were rated independently by two radiologists. SNR estimations were performed for all MRA protocols. RESULTS The use of high PIF allowed to shorten acquisition time from 2:09 min down to 1:13 min and to increase the anatomic coverage while maintaining or even increasing spatial resolution down to 0.46×0.46×0.98 mm(3). The larger anatomic coverage that was achieved with the use of high PIF allowed for visualization of vascular structures that were not covered by the standard protocols. Despite the resulting lower SNR using high PIF, image quality was constantly rated to be adequate for diagnosis or better in all cases. CONCLUSION The use of high PIF yielded diagnostic image quality and allowed to increase the anatomic coverage while maintaining or even improving spatial resolution and shortening the acquisition time.

Value and risk of laparoscopic surgery in hemophiliacs—experiences from a tertiary referral center for hemorrhagic diatheses

PurposeLaparoscopic surgery (LS) is gaining popularity worldwide because of benefits like faster recovery, earlier hospital discharge, and better cosmetic results. In hemophiliacs, surgery in general harbors an increased risk for severe complications. Whether LS or conventional surgery (CS) should be recommended in these patients is controversial and therefore the issue of our present study.MethodsWe performed a retrospective matched-pair analysis including laparoscopically operated non-hemophiliacs (LONH), laparoscopically operated hemophiliacs (LOH), and conventionally operated hemophiliacs (COH) concerning duration of surgery, drainages, hospital stay, complications, factor use (VIII, IX, and X), and blood values. Mann-Whitney U test was used (significance level P = 0.05).ResultsNo significant differences were found in duration of surgery and drains in laparoscopically or conventionally operated hemophiliacs versus matched pairs. Complication rate did not differ among the different groups.Concerning the total duration of hospital stay (t-DHOS) and the postoperative duration of hospital stay (p-DHOS), there was no statistical difference between LOH versus matched LONH. However, in COH versus matched LOH, a longer time was required for preparation and recovery (t-DHOS, P = 0.04; p-DHOS, P < 0.001).Also, the median factor supply perioperatively including the day of surgery did not differ between laparoscopically versus conventionally operated hemophiliacs.ConclusionsOur study underscores the safety and benefits of laparoscopic procedures in hemophiliacs by showing a significantly shorter hospital stay for these patients resulting in reduced therapeutic costs and a faster mobilization. Still, the surgical and perioperative management of hemophiliacs continues to be a challenge requiring an experienced interdisciplinary team.

Impact of CCR7 on the gastrointestinal field effect.

Standardized intestinal manipulation (IM) leads to local bowel wall inflammation subsequently spreading over the entire gastrointestinal tract. Previously, we demonstrated that this so-called gastrointestinal field effect (FE) is immune mediated. This study aimed to investigate the role of CCR7 in IM-induced FE. Since CCR7 is expressed on activated dendritic cells and T cells and is well known to control their migration, we hypothesized that lack of CCR7 reduces or abolishes FE. Small bowel muscularis and colonic muscularis from CCR7(-/-) and wild-type (WT) mice were obtained after IM of the jejunum or sham operation. FE was analyzed by measuring gastrointestinal transit time of orally given fluorescent dextran (geometric center), colonic transit time, infiltration of MPO-positive cells, and circular smooth muscle contractility. Furthermore, mRNA levels of the inflammatory cytokine IL-6 were determined by RT-PCR. The number of dendritic cells and CD3+CD25+ T cells separately isolated from jejunum and colon was determined in mice after IM and sham operation. There was no significant difference in IL-6 mRNA upregulation in colonic muscularis between sham-operated WT and CCR7(-/-) mice after IM. Contractility of circular muscularis strips of the colon was significantly improved in CCR7(-/-) animals following IM and did not vary significantly from sham-operated animals. Additionally, inflammation of the colon determined by the number of MPO-positive cells and colonic transit time was significantly reduced in CCR7(-/-) mice. In contrast, jejunal contractility and jejunal inflammation of transgenic mice did not differ significantly from WT mice after IM. These data are supported by a significant increase of CD3+CD25+ T cells in the colonic muscularis of WT mice after IM, which could not be observed in CCR7(-/-) mice. These data demonstrate that CCR7 is required for FE and postoperative ileus. CCR7 indirectly affects FE by inhibiting migration of activated dendritic cells and of T cells from the jejunum to the colon. These findings support the critical role of the adaptive immune system in FE.

Establishing a biomarker for postoperative ileus in humans - Results of the BiPOI trial.

AIMS Postoperative ileus (POI) is a frequent complication after abdominal surgery, resulting from an inflammation of the muscularis externa (ME). So far no valid biomarker for occurrence, duration or intensity of POI exists. Extravasation of monocytes and neutrophils from blood circulating into the postoperative ME is well known as a hallmark of POI. In a previous study we demonstrated that a low abundant subset of TH1 cells, activated by IL-12, can be detected in the peripheral blood of a small subset of patients in response to abdominal surgery. The aim of the present study was to investigate if these specific TH1 cells, IL-12 or circulating leukocyte levels could act as a valid marker for POI occurrence. MAIN METHODS At different time points, blood samples of patients undergoing abdominal or extraabdominal surgery were collected. Serum levels of IL-12 or TH1 cells as well as neutrophils and monocytes were analyzed. Data were compared between both groups and correlated with clinical signs of POI. KEY FINDINGS Time until first flatus and defecation as well as solid food tolerances are delayed after abdominal compared to extraabdominal surgery. Circulating IL-12 levels and numbers of TH1 cells, neutrophils and monocytes did not differ between both groups. SIGNIFICANCE While previous experiments indicated that specific TH1 cells play a crucial role in POI dissemination, our present data from a larger human cohort demonstrate that they do not seem to be suitable to distinguish between abdominal and extraabdominal surgery. Furthermore neither TH1 cells nor leukocytes or serum IL-12 levels are appropriate biomarkers for POI in a clinical setting.