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Parasites have coevolved with humans. Several of them colonize the human body and establish a symbiotic relationship. Other parasites cause severe and lethal diseases. Prevalence of parasitic infections is decreased in highly industrialized countries, largely due to enforced hygienic practices. In contrast, parasites cause significant morbidity and mortality in parts of the world with barriers to effective public hygiene. Some parasites have emerged as potent pathogens in specific patient populations, such as immune suppressed individuals, regardless of sanitation. This article reviews common parasites encountered in clinical practice and, in the setting of host-parasite symbiosis, discusses their immune regulatory role.

Background Patients with inflammatory bowel disease have higher incidence of airway hyperresponsiveness compared to the general population. Lung inflammation leading to airway hyperresponsiveness causes illnesses for more than ten percent of the population in USA. Aims We investigated the lung response to bacterial endotoxin in colitic mice. Methods Rag-1 mice were transplanted with negatively selected splenic T cells. Some mice groups were treated with NSAID to develop colitis. All mice were treated with bacterial endotoxin and necropsied 3 weeks later. Results Colitic mice developed intensified lung inflammation on day 21 of treatment with bacterial endotoxin. Pulmonary lymphocytes from colitic mice displayed a proinflammatory cytokine profile, expressed high ICAM1 and low FoxP3. CD11c+, CD8+ cells bound and responded to non-systemic antigens from gut-localized microbiota and had higher expression of TLR4. Conclusions Colitic mice developed exacerbated lung inflammation in response to bacterial endotoxin compared to non-colitic mice. Proinflammatory cytokines from pulmonary lymphocytes induced high expression of ICAM1 and suppressed FoxP3 on CD4+ cells. CD11c+, CD8+ cells binding and responding to gut-localized antigens as well as high expression of TLR4 indicate innate and adaptive lung response to bacterial endotoxin. Inflammatory cells from colons of colitic mice homed in the lungs as well as the intestine suggesting recirculation of sensitized immunocompetent cells. These data support our hypothesis that colitis intensifies lung inflammation.

Inflammatory bowel disease (IBD) comprises a group of chronic, intestinal inflammatory disorders, including ulcerative colitis and Crohn's disease. IBD is characterized by periods of relapse and remission. Long-term progressive intestinal inflammation can result in severe and devastating complications, such as intestinal strictures and/or fistulae. Immune suppressive medications with potent side effects are often used to control inflammation and limit disease activity. Laboratory tests guide various decisions in clinical management of IBD. We discuss tests used to diagnose IBD, assess for relapse or remission, monitor the effectiveness of therapeutic regimen, screen for the maintenance of health, and diagnose or prevent complications.

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.

Background Achieving mixed chimerism suppresses donor T cell alloreactivity and reduces graft-versus-host disease (GVHD)-related mortality after bone marrow transplantation (BMT). Mixed hematopoietic chimerism is the only condition proven to lead to immune tolerance after transplantation. It can be achieved with protocols utilizing chemotherapeutic agents or strategies that block T cell activation or deplete host T cells. Selective irradiation of the thymus or lymphoid organs can also lead to mixed hematopoietic chimerism. After total lymphocyte irradiation (TLI), mixed chimerism is mediated by host iNKT lymphocytes and the T helper 2 (Th2) cytokine IL4 generated by those cells. IL4 signals through IL4 receptor (IL4R) and STAT6. After a toxic myeloablative pretransplant regimen, total body irradiation (TBI), intestinal immune conditioning with helminthic commensals regulates the host immune system and promotes a transient mixed chimerism. Conditioning with helminths also induces IL4 production by host cells and regulates GVHD while preserving the graft-versus-tumor effect. We hypothesize that induction of host Th2 pathway is critical for achieving mixed chimerism by intestinal immune conditioning Methods We evaluated the role of recipient Th2 signaling in the establishment of mixed chimerism in an MHC I/II major mismatch (H2b→H2d) model that utilizes TBI. Three weeks after infection with the mouse nematode, Heligmosomoides polygyrus-bakeri (Hpb), GVHD was induced by the delivery of T cell-depleted bone marrow (TCD-BM) and splenic T cells from uninfected WT C57BL/6 (MHC:H2b) donors into lethally-irradiated WT BALB/c, interleukin 4 (IL4) -/-, IL4Rα-/- and STAT6-/- recipients (MHC: H2d). Cellular composition for donor vs recipient cells, GVHD-mediated inflammation in end-organs (colon and lung), and survival of mice in each setting were assessed Results In 3 models of disruption of the Th2 pathway, we demonstrated that Th2 signaling in the host is essential for the establishment of mixed chimerism. Helminth infection promotes mixed chimerism in WT BALB/c BMT recipients; recipient T cells constitute 3-5% of peripheral population at 6 days post-BMT, whereas recipient T cells constitute Conclusions Intestinal immune conditioning with helminths promotes mixed chimerism after toxic, host cell depleting myeloablative TBI and regulates lethal GVHD following BMT. Host cell Th2 pathway is critical for achieving mixed chimerism. Helminths stimulate CTLA4 - a cellular regulatory protein known to promote mixed chimerism after BMT- in a Th2 dependent manner Disclosures Blazar: Kadmon Corporation, LLC: Consultancy, Research Funding.

Production of TGF-β by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-β generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-β generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell–inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β–dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-β and is associated with TGF-β–dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-β–dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-β secretion, TGF-β–dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-β. In contrast, TGF-β is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3− CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4–mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-β generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature.Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed.One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate with treatment of GVHD after LT was 84% with high-dose steroids alone, 75% to 100% with regimens using dose increases of calcineurin inhibitors, and 55% with IL-2 antagonists. Mortality was 25% in small case series using the CD2-blocker alefacept or TNF-α antagonists.Age older than 50 years and hepatocellular carcinoma appear to be risk factors for GVHD. Hepatitis C may be protective. High-dose steroids and calcineurin inhibitors are ineffective in the treatment of GVHD after LT. CD2-blockers and TNF-α antagonists appear promising. We propose a diagnostic algorithm to assist clinicians in managing adults with GVHD after LT.

Helminths down-regulate inflammation and may prevent development of several autoimmune illnesses, such as inflammatory bowel disease. We determined if exposure to the duodenal helminthHeligmosomoides polygyrusestablishes cytokine pathways in the distal intestine that may protect from intestinal inflammation. Mice received 200H. polygyruslarvae and were studied 2 weeks later. Lamina propria mononuclear cells (LPMC) were isolated from the terminal ileum for analysis and in vitro experiments. Mice withH. polygyruswere resistant to trinitrobenzenesulfonic acid (TNBS)-induced colitis, a Th1 cytokine-dependent inflammation.Heligmosomoides polygyrusdid not change the normal microscopic appearance of the terminal ileum and colon and minimally affected LPMC composition. However, colonization altered LPMC cytokine profiles, blocking gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 release but promoting IL-4, IL-5, IL-13, and IL-10 secretion. IL-10 blockade in vitro with anti-IL-10 receptor (IL-10R) monoclonal antibody restored LPMC IFN-γ and IL-12 p40 secretion. IL-10 blockade in vivo worsened TNBS colitis inH. polygyrus-colonized mice. Lamina propria CD4+T cells isolated from colonized mice inhibited IFN-γ production by splenic T cells from worm-free mice. This inhibition did not require cell contact and was dependent on IL-10.Heligmosomoides polygyruscolonization inhibits Th1 and promotes Th2 and regulatory cytokine production in distant intestinal regions without changing histology or LPMC composition. IL-10 is particularly important for limiting the Th1 response. The T-cell origin of these cytokines demonstrates mucosal regulatory T-cell induction.

Molecular and immunologic mechanisms underlying inflammation in inflammatory bowel disease (IBD) are largely unknown. Recent studies have helped better characterize genetic and environmental factors associated with colitis. Discoveries of genetic variants have confirmed that IBD is a bacteria and cytokine-driven pathologic immune response. Data have demonstrated that certain T cell subsets are important in executing the inflammatory cascade. Insufficient regulatory cell activity or modulatory cytokine production results in unrestrained inflammation. Biologic agents that block inflammatory cytokines (anti-TNFalpha antibodies) have been used successfully to treat IBD. Recent advances have also identified mucosal regulatory pathways.

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)–infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β–generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β–dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β–mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β–dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-beta, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-beta release. As TGF-beta exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-beta signaling in helminthic modulation of intestinal immunity. T cell TGF-beta signaling is interrupted in TGF-beta receptor II dominant negative (TGF-betaRII DN) mice by T-cell-specific over-expression of a TGF-betaRII DN. We studied LPMC responses in WT and TGF-betaRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-beta signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-beta-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-betaRII DN mice. Thus, T cell TGF-beta signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-gamma generation and H. polygyrus-mediated suppression of chronic colitis.

Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly proinflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune type inflammatory diseases are associated with IL-17 release. Because helminths protect from these diseases, we examined IL-17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL-17 production by lamina propria mononuclear cells (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL-17A mRNA by MLN cells and inhibits IL-17 production by cultured LPMC and MLN cells. Helminth exposure augments IL-4 and IL-10 production. Blocking both IL-4 and IL-10, but not IL-10 alone, restores IL-17 production in vitro. Colonization of colitic IL-10-deficient mice with H. polygyrus suppresses LPMC IL-17 production and improves colitis. Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation.

Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFbeta production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFbeta, but not TNF-alpha or IL-12. The TGFbeta derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFbeta secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFbeta through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.

Introduction.Graft versus host disease (GVHD) is a frequent and severe complication of allogeneic bone marrow transplantation (BMT). Novel and less toxic treatment regimens are needed to suppress GVHD and preserve graft versus tumor (GVT). Self-limited intestinal helminth colonization stimulates host regulatory T cell (Treg) subsets. The intestine is a prime organ in GVHD generation, with Tregs playing a pivotal role in controlling GVHD. Treg-mediated suppression of GVHD preserves GVT. We hypothesized that self-limited intestinal colonization with helminths protects BMT mice from lethal acute GVHD and preserves the GVT. Methods. Three weeks after administering 3rd stage adult Heligmosomoides polygyrus larvae into 5-6 week old male WT Balb/C recipient mice (H2d), we initiated H2b→H2d MHC I/II mismatch model of acute GVHD by total body irradiation (TBI; 850 cGy) and administration of total splenic T cells and T cell depleted (TCD) bone marrow (BM) cells from male C57BL/6 WT (MHC: H2b) donors into uninfected control and helminth-infected male wild-type (WT) Balb/C (MHC: H2d) bone marrow recipients. In certain experiments, we used donor T cells from TGFβ RII dominant negative (DN) (TGFβ RII DN) mice (MHC: H2b) whose T cells are unresponsive to TGFβ-mediated immune regulation due to over-expression of a truncated TGFβ receptor II. Th1 (IFNγ, TNFα) cytokine generation was analyzed by ELISA. Splenic and mesenteric lymph node (MLN) cells were stained for H2b, H2d, T cell surface markers and FoxP3. Tissues were analyzed for GVHD-related inflammation. GVT was assessed in uninfected and helminth-infected BMT recipients by administration of luciferase expressing A20 leukemia/lymphoma cells (A20-luc; H2d) and IVIS imaging. Statistical and survival difference between groups was determined by Student’s t-test and Kaplan Meier curves, respectively. Results. Helminths increased ~3-fold CD4 T cell and FoxP3+ Treg TGFβ generation (p15 weeks survival of 40% of recipients, while all uninfected BMT recipient mice died of GVHD (p Conclusions. Our results show that (1) helminths stimulate TGFβ producing host T cells and FoxP3+ Tregs that survive BMT conditioning with TBI; (2) helminths regulate GVHD by inducing donor Tregs and in a TGFβ dependent manner; (3) helminths preserve GVT. With a safe side-effect profile, helminths or helminth products have the potential to be investigated as an alternative strategy to prevent or treat GVHD. Disclosures No relevant conflicts of interest to declare.

We investigated whether inhibitory natural killer cell receptor (iNKR) expression contributes to impaired antigen-specific cytotoxicity and interferon-gamma (IFN-gamma) production by CD8 T cells during chronic infection. iNKR immunoglobulin-like transcript-2 (ILT2/CD85j) is expressed on 40-55% of cytomegalovirus (CMV)-, Epstein-Barr virus (EBV)- and human immunodeficiency virus (HIV)-specific CD8 T cells in both healthy and HIV-infected donors. Other iNKRs (CD158a, b1, e1/e2, k, CD94/NKG2A) are expressed on only a small minority of CD8 T cells and are not preferentially expressed on tetramer-staining virus-specific cells. In normal donors, ILT2 is expressed largely on perforin(+) CD27(-) effector cells. However, in HIV-infected donors, only a third of ILT2(+) cells are also perforin(+). In both normal and HIV-infected donors, ILT2(+) cells are prone to spontaneous apoptosis. Therefore, ILT2 is normally expressed during effector cytotoxic T-lymphocyte (CTL) differentiation, but can also be expressed when effector maturation is incomplete, as in HIV infection. The effect of ILT2 on CD8 cell function was assessed by preincubating effector cells with ILT2 antibody. While blocking ILT2 engagement has no appreciable effect on cytotoxicity, it increases antiviral IFN-gamma production by approximately threefold in both normal and HIV-infected donors. Thus, ILT2 expression, increased on antiviral CD8 cells in chronic infection, may interfere with protective CD8 T-cell function by suppressing IFN-gamma production.

Melanin-concentrating hormone (MCH) is localized mainly in the brain, but it is also found in the intestine. MCH plays a clear role in feeding behavior. Recent data suggests that MCH and the MCH receptor 1 mediate intestinal inflammation in mice. Two diverse MCH receptor 1 antagonists (DABA-821 and DABA-822) have been developed for pharmacological testing. DABA-821 penetrates the blood-brain barrier, while DABA-822 does not. Study Aim: Our goal was to test DABA-821 and DABA-822 in a murine model of TNBS colitis. The efficacy of these compounds was compared to Dexamethasone (Dex).Methods: Female BALB/c mice (n=37) were randomized to receive an intracolonic enema of PBS, 50% ethanol/PBS, or 20 mg/kg TNBS in 50% ethanol. On day 1 (five hours after the enemas) mice were given Vehicle, 30 mg/kg of DABA-821, 30 mg/kg of DABA-822, or 1 mg/kg of Dex by orogastric gavage. Test drugs were also administered bid on days 2 through 6. On day 7, mice were euthanized. The colon was analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity and histological pathology. Body and spleen weights were also determined. Results:Macroscopic colonic scores (combination of lesions, diarrhea, adhesions, thickness) were significantly increased in TNBS treated mice, as compared to PBS or 50% ethanol treated animals. These scores were attenuated by 53 to 75% in mice treated with the MCH-1 receptor antagonists. Similar efficacy was found with Dex. Colonic ulceration was clearly apparent in the Vehicle/TNBS treatment group, but ulcer severity was significantly reduced in mice treated with the MCH receptor 1 antagonists. Mean colonic ulcer scores were: 4.7 (Vehicle/TNBS), 2.4 (DABA-821), 2.9 (DABA-822) and 2.8 (Dex). As compared to their vehicle treated cohorts, colons were significantly longer, but weighed less, in drug treated mice. Colonic MPO activity was nearly normalized in mice treated with Dex, but only partially attenuated by treatment with the MCH receptor 1 antagonists. Colonic histology scores were significantly reduced (p < 0.05 vs. Vehicle) in all drug treatment groups. Vehicle/TNBS treated mice lost significant weight throughout the study, as compared to PBS treated animals. None of the treatments normalized this weight loss. Reduced spleen weights were observed in Dex treated mice, as well as in mice treated with DABA-821 and 822. Summary: Two diverse MCH receptor 1 antagonists attenuated various parameters of TNBS-induced colitis in mice. The anti-colitis profile of these antagonists was similar to Dex. Conclusion:MCH receptor 1 antagonismmay represent an effective therapeutic approach for intestinal inflammation.

in C.rodentium infection remain to be seen. Method and Result: C. rodentium which express GFP constitutively (CR/GFP) has been established by the transformation with the GFPexpression vector. The expression of GFP was confirmed by flow cytometry and fluorescence microscopy. To examine the localization of C.rodentium, 3-week-old wild-type mice were orally inoculated with CR/GFP. CR/GFP were detected on the cell surface at the colon at day 3 and some were also detected in the CD11b positive cells such as macrophages or dendtiric cells of the colon. The bacterial number in the section of the infected colon and in the feces were increased until day 14. To examine the antigen-specific immune response of CD4 + T cell in C.rodentium infection, OVA-expressing C.rodentium which produce chicken ovalbumin constitutively (CR/OVA) have also been established by the transformation with OVA producing plasmid. The antigenic expression of OVA was confirmed by western blot and T cell-proliferation assay. IgM and IgG response against OVA were detected 2 weeks after oral infection with CR/OVA. Next, to examine the C.rodentium-specific T cell response, CFSE systems were utilized. Wild-type mice were infected with CR/OVA at day 1. CFSE labeled OVA-specific CD4+ T cells (OT-II cells) were adoptively transferred at day 12 and then, MLN were collected at day 15. Proliferation of OVA-specific CD4+ T cells were demonstrated by the detection of multiple cell CD4+ division of CFSE-loaded transgenic T cells. Moreover, enhanced cytokine production of IFN-γ and IL-4 were also detected after In Vitro stimulation with OVA. Conclusion: These studies show the natural course and host immune response in C. rodentium infection. These model systems are useful to examine the mucosal immunity against C.rodentium infection in detail.

Helminths are immune modulators that down-regulate colitis in inflammatory bowel disease. In animal models, intestinal bacteria drive colitis and in humans certain alleles of the LPS receptor protein TLR4 increase inflammatory bowel disease susceptibility. To understand helminthic immune modulation in the gut, we studied the influence of intestinal Heligmosomoides polygyrus colonization on LPS-induced lamina propria mononuclear cell (LPMC) cytokine responses in mice. LPS did not stimulate TGFβ production from LPMC of uninfected mice. LPS strongly induced LPMC from worm-infected animals to secrete TGFβ, but not TNF-α or IL-12. The TGFβ derived from mucosal T cells. Helminth infection up-regulated TLR4 expression only in lamina propria T cells. LPMC from worm-infected TLR4 mutant animals did not respond to LPS, suggesting that LPS required TLR4 to stimulate TGFβ secretion. Thus, during helminth infection, LPS challenge induces mucosal T cells to make TGFβ through a TLR4-dependent process without promoting synthesis of proinflammatory cytokines.