Colon Lymph Nodes Research Articles

A Pilot Study of Colon Lymph Node Counts on Faxitron (radiographs) Compared with Pathology Reports

A Pilot Study of Colon Lymph Node Counts on Faxitron (radiographs) Compared with Pathology Reports

Contribution of FOXC1 to the progression and metastasis and prognosis of human colon cancer.

636 Background: Distant metastasis remains the most common causes to death of colon cancer. Thus it is crucial to identify the molecular markers associated with the progression and metastasis of this disease. Recent evidence for overexpression of FOXC1 in several types of human cancer suggests that it might play a key role in tumor biology. However, the clinical significance of FOXC1 signaling in human colon cancer pathogenesis remains unknown. Methods: We investigated FOXC1 expression in 203 cases of primary colon cancer and matched normal colon tissue and lymph node matastasis in a tissue array. The underlying mechanisms of altered FOXC1 expression and the impact of this altered expression on colon cancer growth and metastasis was explored both in vitro and in vivo. Results: We found elevated expression of FOXC1 protein in cancereous tissue and lymph node metastases than adjacent normal colonic tissues. Overexpression of FOXC1 was associated with higher clinical stage, T stage, lymph node metastasis and presence of distant metastasis. FOXC1 served as an independent prognostic marker whose expression levels correlated with poorer metastasis-free survival (MFS) and poorer overall survival (OS). A Cox proportional hazards model revealed that FOXC1 expression was an independent prognostic factor in multivariate analysis. Experimentally, FOXC1 silencing significantly inhibited the growth and metastasis of colon cancer cells in vitro and in vivo. FOXC1 transcriptionally regulates SNAIL1, contributing to epithelial-to-mesenchymal transition and metastasis in colon cancer cells. Conclusions: Dysregulated expression of FOXC1 may play a critical role in colon cancer progression and metastasis. Thus, FOXC1 may serve as a candidate prognostic biomarker and therapeutically targeted.

Conversion chemotherapy combined with surgical treatment of unresectable advanced gastric cancer.

189 Background: Local advanced gastric cancer which could not receive R0 resection, or gastric cancer with single distant metastasis usually received palliative chemotherapy or entered into various clinical trials, and surgery usually roled as a symptomatic treatment. This study is to investigate the efficacy and safety of PCF chemotherapy combined with surgery in the treatment of these patients. Methods: From 2007.8 to 2012.8, 78 cases of local advanced gastric cancer which can not be treated with R0 resection(T4N2~3M0) or gastric cancer with single distant metastases(M1) were prospectively analysed. Patients were treated with 2~4 cycles of combined chemotherapy with paclitaxel (150mg/m2,d1), cisplatin(25mg/m2, d1~3) and 5-fluorouracil (750 mg/m2, d1~3) ( repeated every 3 weeks), and were then treated with cytoreductive surgery: mainly treated with radical resection of gastric tumor, combined with extended lymph node dissection, pancreaticoduodenal resection, colon resection, ovariectomy, liver resection and tumor radio frequency, followed by another 2~4 cycles of postoperative PCF chemotherapy.The treatment completion rate, patients’ tolerance and overall survival time were analyzed. Results: 56 patients (71.8%) accomplished chemotherapy and surgical resection as planned. 47 cases had R0 resection(60.3%). Grade 3/4 toxic effects included bone marrow suppression(24.4%) and gastrointestinal reaction(37.2%), the overall response rate (CR+PR) was 73.1%(CR 2 cases, PR 55 cases). Survival analysis: the median survival time was 23.4 months. 1-year and 3-year survival rate was 68.1% and 33.5%. The OS of patients with surgical resection was much longer than that of the non-surgery group.(36.1 VS 10.0 months, P<0.01). The OS of local advanced group was 38.6 months, and was significantly longer than 20.7 months of the distant metastasis group (P<0.01), however, it had no significant difference compared to 31.3 months of the distant metastasis group with R0 resection. Conclusions: PCF chemotherapy combined with surgical resection were safe and effective, and can make survival benefits for patients with local advanced gastric cancer or gastric cancer with single distant metastasis.

Can Immunopathology Explain Why Metastasizing Lung Cancer Cells Manifest Ubiquity in the Blood Stream but Selectivity in Lymph Node Colonization?

It has been calculated that metastasizing lung cancers are numbered in millions. It has also been argued that lymph nodes occupy the status of organs in cancer metastasis. Accordingly, both the tissues now generally regarded as organs as well as lymph nodes, which are of that same status, should all be haphazardly showered by circulating cancer cells. On the contrary, these two sets of organs exhibit very conspicuous diversity in their colonization patterns. Thus, the better known organs generally exhibit scattered secondaries all over the body while the lymph nodes are selectively affected. Thus, in the words of Willis, a foremost cancer authority, lung cancers “often” exhibit discrete deposits in the abdominal lymph nodes, “these diminishing in centrifugal order.” Indeed, such an order is not known as regards, say, the liver, adrenal gland, kidney and ovaries. Therefore, is Nature showing signals which ought to be decoded? Here, I argue that this is possible. Moreover, the welcome expectation is that such a study of lung cancer can usher in an immunological breakthrough which may point to target therapy and thereby conduce to cancer cure.

多発リンパ節結核，大腸癌を合併した患者に生じた結節性紅斑の 1 例

多発リンパ節結核，大腸癌を合併した患者に生じた結節性紅斑の 1 例

Salmonella Prevalence and Microbiological Contamination of Pig Carcasses and Slaughterhouse Environment.

In seven EC swine abattoirs Salmonella prevalence (ISO 6579/2002) and serotypes of 25 piglets, 61 finishing pigs (lymph nodes, colon content, carcass and liver surface) and slaughterhouse environments (scalding water, surfaces in contact with meat and not in contact with meat) were investigated. Moreover, aerobic colony count [total viable count (TVC); ISO 4833] and Enterobacteriaceae (ISO 21528-2) of piglets and finishing pigs’ carcasses were evaluated, and the results compared with EU process hygiene criteria (Reg. EC 2073/2005). Salmonella was not isolated in any of the piglets samples. Prevalence differed between slaughterhouses (P<0.5), and Salmonella was isolated from 39 of 244 samples of finishing slaughtered pigs (15.9%) and from 4 of 45 environmental samples (8.9%). In pig samples, carcasses showed the highest prevalence (18%) followed by colon content (14.8%), lymph nodes (13%) and liver (1.6%). S. Anatum was the most prevalent serotype (71.8%), followed by S. Derby (33.3%), S. Bredeney (5%) and S. Holcomb (2.5%). Between environmental samples, S. Anatum (50%), S. Bredeney and S. Derby (25%) were identified. Total viable mean counts (log10 CFU/cm2) of carcass surfaces ranged from 4.6 and 5.7 for piglets, and from 4.6 and 5.9 for finishing pigs, while Enterobacteriaceae ranged between 1.1 and 5 for piglets and between 2.1 and 5.3 for finishing pigs. These results were not in compliance with EU performance criteria. Total aerobic viable counts and Enterobacteriaceae mean levels of environmental samples appeared critical, particularly referred to surfaces in contact with meat (splitting equipment) and indicated an inadequate application of good manufacturing and hygiene practices during slaughtering and sanitisation.

Administration of a Tryptophan Metabolite, Indole-3-Carboxaldehyde, Reduces Graft Versus Host Disease Morbidity and Mortality and Enhances Gastrointestinal Barrier Function in a Murine Model of Allogeneic Bone Marrow Transplantation

Background:Allogeneic bone marrow transplantation for patients with hematological malignancies is curative, but the success of the procedure is limited by graft versus host disease (GvHD). Donor T-cells present in the graft are critical for the graft-versus-leukemia effect (GvL) of the transplant and important in facilitating bone marrow reconstitution, but also contribute to development of GvHD, and the risk of GvHD increases dramatically when the donor and recipient are not matched at all of the HLA loci. Hence, there is an urgent need for new approaches to curb GvHD and facilitate transplantation of HLA mismatched grafts to improve patient outcomes. Here, we have used an MHC-mismatched mouse model of GvHD to develop a novel and powerful approach to improve the success of allogeneic bone marrow transplantation by limiting GvHD. We identified a tryptophan metabolite, indole-3-carboxaldehyde (ICA), a dietary component present in foods such as collard greens and broccoli, that prevents lethal GvHD and allows normal engraftment by allogeneic donor bone marrow when fed to transplant recipients for the first few weeks after transplant.Methods:Lethally irradiated B10.BR (H2k) mice were transplanted with 3 x 106 T cell depleted bone marrow cells (TCD-BM) alone or the combination of TCD-BM plus 2 x 106 purified T cells from B6 (H2b) donor mice. Mice received daily gavage with 100 mg/kg or 150 mg/kg ICA or vehicle through day 38 post-transplant. Survival and clinical manifestations of GvHD were monitored through day 62. Histopathology of the gut, cytokines in serum and colon homogenates, intracellular cytokine staining of donor T-cells and bacterial counts in mesenteric lymph nodes (using blood agar plates) were measured in a separate cohort of experimental mice euthanized on day 20. Additionally, a secondary transplant was conducted to test the allo-proliferative capacity (in vivo CFSE dilution assay) and GvHD activity of T-cells from spleens of mice in the TCD-BM + T cells + 150 mg/kg ICA group that survived to day 62, compared to B6 T cells, in combination with fresh B6 TCD-BM, in B10.BR recipients.Results and Conclusion:Figure 1 shows survival curves for mice transplanted with TCD-BM + T-cells that were fed vehicle (red), 100 mg/kg/day of ICA (blue), or 150 mg/kg/day of ICA (green) by oral gavage. Only 7% of the recipients of TCD-BM + T cells treated with vehicle only survived to day 46. ICA administration improved survival in a dose-dependent manner: recipients given 100 mg/kg/day of ICA had 20% survival at day 52 (**p = 0.009) and administration of 150 mg/kg/day of ICA resulted in 83% survival of recipients of TCD-BM + T cells (***p <0.001). ICA was well tolerated without serious toxicity in recipients of BM grafts without GvHD-causing T-cells (thin black solid line). ICA-treated recipients of TCD-BM + T cells had improved thymopoiesis and decreased levels of inflammatory cytokines. Histological analysis of colonic tissue from these ICA-treated recipients also showed marked reduction of GvHD pathology and decreased bacterial colonization of mesenteric lymph nodes (MLN) compared to vehicle-treated control animals (Figure 2, *p < 0.01), indicating enhanced gastrointestinal barrier function. T cells recovered from ICA-treated TCD-BM + T cell transplant recipients at day 62 had been rendered tolerant to recipient type alloantigens in secondary transplant in vivo assays as shown by reduced proliferation of CFSE-stained T cells and lack of GvHD activity in secondary B10.BR recipients.These data indicate that enteral administration of ICA, a natural compound present in food, causes a dramatic reduction of GvHD in a MHC mismatched model of allogeneic bone marrow transplantation. We postulate that this effect is mediated through activation of the aryl hydrocarbon receptor in innate lymphoid cells in the lamina propria of the gut, stimulating regeneration of the gut epithelium and reducing trans-epithelial migration of gut bacteria that contribute to GvHD. Further development and exploration of the mechanism by which ICA treatment reduces GvHD could have a major impact on improving the safety of allogeneic bone marrow transplantation, and increase the availability of donors for those patients who currently lack an HLA matched sibling or volunteer donor. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Poly d,l-lactide-co-glycolide (PLGA) nanoparticle-encapsulated honeybee (Apis melifera) venom promotes clearance of Salmonella enterica serovar Typhimurium infection in experimentally challenged pigs through the up-regulation of T helper type 1 specific immune responses

Honeybee (Apis melifera) venom (HBV), which includes melittin and lipid-soluble ingredients (chrysin and pinocembrin), elicited increases in the CD4+/CD8+ T lymphocyte ratio, relative mRNA expression levels of the T helper type 1 (Th 1) cytokines (interferon-γ and IL-12) and reinforced viral clearance of an experimental porcine reproductive and respiratory syndrome (PRRS) virus infection in our previous study. On the basis of that previous study, we have now developed poly-d,l-lactide-co-glycolide (PLGA)-encapsulated HBV nanoparticles (P-HBV) for longer sustained release of HBV. We administered P-HBV to pigs via the rectal route, and then evaluated the potential immune-enhancing and bacterial clearance effects of P-HBV against Salmonella enterica serovar Typhimurium. The CD4+/CD8+ lymphocyte ratio, proliferative capacity of peripheral blood lymphocytes and relative mRNA expression levels of IFN-γ and IL-12 (produced mainly by Th1 lymphocytes) were significantly increased in the P-HBV group up to 2 weeks post-administration of P-HBV. After S. Typhimurium infection, the P-HBV group showed a marked reduction in microbial burden in feces and all tissue samples (including the ileum, cecum, colon, and mesenteric lymph node (MLN)), a significant increase in Th 1 cytokines (IFN-γ, IL-2, and IL-12) and a marked decrease in a Th 2 cytokine (IL-4) in all tissue samples and peripheral blood lymphocytes. Thus, P-HBV may be a promising strategy for immune enhancement and prevention of S. Typhimurium or other bacterial infections.

Impact of perioperative symbiotic therapy on infectious morbidity after Hpb Surgery in jaundiced patients: a randomized controlled trial.

This study aimed at evaluating whether the administration of symbiotic therapy in jaundiced patients could reduce their postoperative infectious complications. The study was conducted between November 2008 and February 2011. Jaundiced patients scheduled for elective extrahepatic bile duct resection without liver cirrhosis, intestinal malabsorption or intolerance to symbiotic therapy were randomly assigned to receive [Group A] or not [Group B] symbiotics perioperatively. The primary endpoint was the infectious morbidity rate. Forty patients were included in the analysis (20 in each group). The patients in Group B presented a higher overall morbidity (70 vs 50%) and infectious morbidity rate (50 vs 25%), but the differences were not significant. Eleven patients in Group A (Group ndA) and 13 in Group B (Group ndB) did not receive preoperative biliary drainage. The results of the two groups were comparable. Infectious complications were higher in Group B [5 (34%) vs 0, p = 0.030], while the prevalence of natural killer (NK) cells was higher in Group ndA the day before surgery (17% ± 5.1 vs 10% ± 5.3, p < 0.01) and on post-operative day (POD) 7 (13.1% ± 4.1 vs 7.7% ± 3.4, p < 0.01). The rates of lymph node colonization were similar. The symbiotic therapy failed to reduce the rate of infectious morbidity in jaundiced patients. Further studies investigating the place of symbiotic in no-drainage patients are required.

Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa.

The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections.

Fermentable fibres condition colon microbiota and promote diabetogenesis in NOD mice.

Gut microbiota (GM) and diet both appear to be important in the pathogenesis of type 1 diabetes. Fermentable fibres (FFs), of which there is an ample supply in natural, diabetes-promoting diets, are used by GM as a source of energy. Our aim was to determine whether FFs modify GM and diabetes incidence in the NOD mouse. Female NOD mice were weaned to a semisynthetic diet and the effects of FF supplementation on diabetes incidence and insulitis were evaluated. Real-time quantitative PCR was employed to determine the effects imposed to gene transcripts in the colon and lymph nodes. Changes to GM were analysed by next-generation sequencing. NOD mice fed semisynthetic diets free from FFs were largely protected from diabetes while semisynthetic diets supplemented with the FFs pectin and xylan (PX) resulted in higher diabetes incidence. Semisynthetic diet free from FFs altered GM composition significantly; addition of PX changed the composition of the GM towards that found in natural-diet-fed mice and increased production of FF-derived short-chain fatty acid metabolites in the colon. The highly diabetogenic natural diet was associated with expression of proinflammatory and stress-related genes in the colon, while the semisynthetic diet free from FFs promoted Il4, Il22, Tgfβ and Foxp3 transcripts in the colon and/or pancreatic lymph node. PX in the same diet counteracted these effects and promoted stress-related IL-18 activation in gut epithelial cells. 16S RNA sequencing revealed each diet to give rise to its particular GM composition, with different Firmicutes to Bacteroidetes ratios, and enrichment of mucin-degrading Ruminococcaceae following diabetes-protective FF-free diet. FFs condition microbiota, affect colon homeostasis and are important components of natural, diabetes-promoting diets in NOD mice.

Inflammatory cytokines induce vascular endothelial growth factor-C expression in melanoma-associated macrophages and stimulate melanoma lymph node metastasis.

Lymph node colonization by tumor cells is one of the key determinants of melanoma staging and prognosis, and tumor-associated macrophages (TAMs) are the predominant type of inflammatory cell in the tumor environment which secretes vascular endothelial growth factor (VEGF)-C, the most potent lymphangiogenic growth factor. In the present study, to elucidate the mechanism involved in VEGF-C expression in TAMs, murine peritoneal macrophages were co-cultivated with syngeneic B16 melanoma cells to mimic the reciprocal interactions between tumor cells and macrophages found in spontaneous tumors. In the present study, upon contact with tumor cells, macrophages were found to express a higher level of VEGF-C which was associated with an increase in the expression of IL-1β and TNF-α and their receptors. Antibodies against the IL-1β and TNF-α receptors were added to media that had been conditioned by the macrophage-tumor cell co-cultures and inhibition of VEGF-C was observed in macrophages co-cultivated with the tumor cells. Furthermore, when IL-1β and TNF-α were used at a non-toxic level, they enhanced peritoneal lymph node colonization by melanoma cells. Thus, in the present study, macrophagic IL-1β and TNF-α were observed to promote VEGF-C expression in TAMs, as well as melanoma lymph node metastasis, suggesting that inhibiting the signaling between tumor cells and TAMs may be required to inhibit lymphangiogenesis and lymph node metastasis.

FGFR2 is amplified in the NCI-H716 colorectal cancer cell line and is required for growth and survival.

Aberrant kinase activation resulting from mutation, amplification, or translocation can drive growth and survival in a subset of human cancer. FGFR2 is amplified in breast and gastric cancer, and we report here the first characterization of FGFR2 gene amplification in colorectal cancer in the NCI-H716 colorectal cancer cell line. FGFR2 is highly expressed and activated in NCI-H716 cells, and FGFR selective small molecule inhibitors or FGFR2 shRNA strongly inhibited cell viability in vitro, indicating “addiction” of NCI-H716 cells to FGFR2. NCI-H716 growth in a xenograft model was also inhibited by an FGFR small molecule inhibitor. FGFR2 was required for activation of multiple downstream signaling proteins including AKT, ERK, S6RP and NFKB. Inhibition of downstream kinases such as AKT or ERK alone had modest effects on proliferation, whereas combined inhibition of AKT and ERK signaling resulted in a loss of viability similar to FGFR2 inhibition. We identified elevated FGFR2 expression in a small subset of primary colorectal cancer, however FGFR2 amplification was not observed. Although FGFR2 amplification is not common in primary colon cancer or lymph node and liver metastases, other subsets of colorectal cancer such as ascites, from which the NCI-H716 cell line was derived, have yet to be tested. These results suggest that emerging FGFR inhibitor therapeutics may have efficacy in a subset of colon cancer driven by FGFR2 amplification.

Expression of regulatory T cells in jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected with Leishmania infantum.

Using flow cytometry, we evaluated the frequencies of CD4(+) and CD8(+) T cells and Foxp3(+) regulatory T cells (Tregs) in mononuclear cells in the jejunum, colon, and cervical and mesenteric lymph nodes of dogs naturally infected with Leishmania infantum and in uninfected controls. All infected dogs showed chronic lymphadenitis and enteritis. Despite persistent parasite loads, no erosion or ulcers were evident in the epithelial mucosa. The colon harbored more parasites than the jejunum. Frequencies of total CD4(+), total Foxp3, and CD4(+) Foxp3(+) cells were higher in the jejunum than in the colon. Despite negative enzyme-linked immunosorbent assay (ELISA) serum results for cytokines, levels of interleukin-10 (IL-10), gamma interferon (IFN-γ), transforming growth factor beta (TGF-β), and tumor necrosis factor alpha (TNF-α) were higher in the jejunum than in the colon for infected dogs. However, IL-4 levels were higher in the colon than in the jejunum for infected dogs. There was no observed correlation between clinical signs and histopathological changes or immunological and parasitological findings in the gastrointestinal tract (GIT) of canines with visceral leishmaniasis. However, distinct segments of the GIT presented different immunological and parasitological responses. The jejunum showed a lower parasite load, with increased frequencies and expression of CD4, Foxp3, and CD8 receptors and IL-10, TGF-β, IFN-γ, and TNF-α cytokines. The colon showed a higher parasite load, with increasing expression of IL-4. Leishmania infantum infection increased expression of CD4, Foxp3, IL-10, TGF-β, IFN-γ, and TNF-α and reduced CD8 and IL-4 expression in both the jejunum and the colon.

Lymphadenectomy quality measure for colon cancer: Is it working?

6537 Background: Endorsement of the 12 lymph node colon cancer measure has led to improvements in national performance. However, it is unknown whether hospital performance on this measure is associated with improved outcomes. The objectives of this study were to determine whether improvement on this measure impacts stage migration or survival. Methods: Patients in the National Cancer Data Base undergoing resection for stage I-III colon cancer (1995-2011) were identified. Three hospital improvement groups were created using change in median node count over time ( 10). Changes in the ratio of stage III patients over time were compared between groups. A hierarchical Cox model was used to assess the relationship between hospital improvement and 5 year overall survival for stage II patients. Results: A total of 455,155 patients from 1,047 hospitals were identified. Median hospital lymph node counts increased from 10 (IQR 8-10) to 17 (IQR 15-19) over the study period. Increase in stage III patients o...

Differential effects of TLR-2 ligands on CD4+ CD25+ Foxp3+ regulatory cells depending on inflammatory cytokine milieu (IRC4P.489)

Abstract The responsiveness of CD4+CD25+Foxp3+ thymic Tregs (tTregs) towards microbial agents that serve as toll-like receptor (TLR) ligands is unclear. This study investigates the effects of TLR ligands on Tregs. We show that TLR-2 ligands promote IL-2 dependent survival and proliferation of tTregs both in the presence or absence of TCR signals and inflammatory cytokines. The proliferation is directly dependent on TLR-2 expression on Tregs showing that TLR-2 ligands may be involved in Treg proliferation in vivo. Consistent with this, Tlr-2-/- mice harbor fewer Tregs in colon and mesenteric lymph nodes in vivo. However, in the presence of IL-6 and TCR signals, Tregs also acquire effector functions by producing IL-17A. However, they retain their suppressive properties and do not lose Foxp3 expression. Their effector function is dependent on TLR signaling by antigen presenting cells, IL-6 and IL-23 in the milieu, but not on direct TLR-2 signaling by Tregs. IL-17A production in Tregs is also relevant in vivo, as CD4+Foxp3+Tregs are capable of producing IL-17A without losing their suppressive properties during oropharyngeal candidiasis and inflammatory bowel disease. These data show that CD4+Foxp3+ tTregs are a stable lineage of cells, and that TLR-2 ligands promote their proliferation without inducing plasticity. Moreover the data show for the first time, the direct and indirect effects of TLR-2 ligands that differentially regulate tTreg proliferation and effector functions.

Nucleotide-Binding Oligomerization Domain–Containing Protein 2 Controls Host Response to Campylobacter jejuni in Il10−/− Mice

Innate signaling-induced antimicrobial response represents a key protective host feature against infectious microorganisms such as Campylobacter species. In this study, we investigated the role of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in Campylobacter jejuni-induced intestinal inflammation. Specific-pathogen-free Il10(-/-), Nod2(-/-), and Il10(-/-); Nod2(-/-) mice were infected with C. jejuni (10(9) colony-forming units/mouse) 24 hours after a 7-day course of antibiotic treatment. Three weeks later, host responses were determined. The nitric oxide (NO) donor sodium nitroprusside was injected intraperitoneally (2 mg/kg daily) to supplement NO. Although healthy in specific-pathogen-free conditions, Il10(-/-); Nod2(-/-) mice developed severe intestinal inflammation following C. jejuni infection, compared with Nod2(-/-) and Il10(-/-) mice. The onset of colitis was associated with elevated neutrophil accumulation, crypt abscesses, and expression of the endogenous proinflammatory mediators Il-1β, Tnfα, and Cxcl1. Fluorescence in situ hybridization and culture assay showed enhanced C. jejuni invasion into the colon and mesenteric lymph nodes in Il10(-/-); Nod2(-/-) mice, compared with Il10(-/-) mice. C. jejuni-induced bactericidal NO production was reduced in peritoneal macrophages from Il10(-/-); Nod2(-/-) mice, compared with Il10(-/-) mice. Importantly, sodium nitroprusside attenuated C. jejuni-induced colitis in Il10(-/-); Nod2(-/-) mice. Our findings suggest that NOD2 signaling is critical to control campylobacteriosis in Il10(-/-) mice, a process involving NOD2-mediated bactericidal responses.

Multi‐functional plasmacytoid dendritic cells redistribute to gut tissues during simian immunodeficiency virus infection

The objective of this study was to determine the systemic effects of chronic simian immunodeficiency virus (SIV) infection on plasmacytoid dendritic cells (pDCs). pDCs play a critical role in antiviral immunity, but current data are conflicting on whether pDCs inhibit HIV/SIV replication, or, alternatively, contribute to chronic immune activation and disease. Furthermore, previous pDC studies have been complicated by incomplete descriptions of generalized depletion during HIV/SIV infection, and the effects of infection on pDCs outside peripheral blood remain unclear. In scheduled-sacrifice studies of naive and chronically SIV-infected rhesus macaques we evaluated the distribution and functionality of pDCs in multiple tissues using surface and intracellular polychromatic flow cytometry. As previously observed, pDCs were reduced in peripheral blood and spleens, but were also depleted in non-lymphoid organs such as the liver. Interestingly, pDCs accumulated up to fourfold in jejunum, colon and gut-draining lymph nodes, but not in peripheral lymph nodes. Most unexpectedly, SIV infection induced a multi-functional interferon-α, tumour necrosis factor-α, and macrophage inflammatory protein-1β cytokine secretion phenotype, whereas in normal animals these were generally distinct and separate functions. Herein we show a systemic redistribution of pDCs to gut tissues and gut-draining lymph nodes during chronic SIV infection, coupled to a novel multi-functional cytokine-producing phenotype. While pDC accumulation in the mucosa could aid in virus control, over-production of cytokines from these cells could also contribute to the increased immune activation in the gut mucosa commonly associated with progressive lentivirus infections.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Heligmosomoides polygyrus bakeri Infection Activates Colonic Foxp3+ T Cells Enhancing Their Capacity To Prevent Colitis

Helminthic infections protect mice from colitis in murine models of inflammatory bowel disease and also may protect people. Helminths like Heligmosomoides polygyrus bakeri can induce regulatory T cells (Treg). Experiments explored whether H. polygyrus bakeri infection could protect mice from colitis through activation of colonic Treg and examined mechanisms of action. We showed that H. polygyrus bakeri infection increased the number of T cells expressing Foxp3 in the colon. More importantly, Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets isolated from the colon of H. polygyrus bakeri-infected mice prevented colitis when adoptively transferred into a murine model of inflammatory bowel disease, whereas Treg from uninfected mice could not provide protection. Only the transferred colonic Foxp3(+)/IL-10(-) T cells from H. polygyrus bakeri-infected mice readily accumulated in the colon and mesenteric lymph nodes of recipient mice, and they reconstituted the Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets. However, transferred Foxp3(+)/IL-10(+) T cells disappeared. IL-10 expression by Foxp3(+) T cells was necessary for colitis prevention. Thus, H. polygyrus bakeri infection activates colonic Foxp3(+) T cells, making them highly regulatory. The Foxp3(+) T cells that fail to express IL-10 may be critical for populating the colon with the Foxp3(+)/IL-10(+) T cells, which are required to control colitis.