Ulcerative Colitis: Mayer L

Mayer L. · No affiliation provided · Gastroenterology. · Pubmed #15825092 No free full text.

This publication has no abstract.

Brown SJ, Mayer L. · Division of Gastroenterology, Department of Medicine, The Mount Sinai School of Medicine, New York, New York 10029, USA. · Am J Gastroenterol. · Pubmed #17561966 No free full text.

Abstract: Ulcerative colitis (UC) and Crohn's disease (CD), collectively referred to as inflammatory bowel disease (IBD), present with differing histologic and cytokine profiles. While the precise mechanisms underlying the development of IBD are not known, sufficient data have been collected to suggest that it results from a complex interplay of genetic, environmental, and immunologic factors. Animal models of colitis, along with a more detailed understanding of the immune response in the normal bowel, have led to unifying hypotheses regarding the pathogenesis. An inappropriate mucosal immune response to normal intestinal constituents is a key feature, leading to an imbalance in local pro- and anti-inflammatory cytokines. Neutrophil and monocyte influx occurs with subsequent secretion of oxygen radicals and enzymes, leading to tissue damage. Therapy of IBD has improved and expanded as the understanding of disease mechanisms has evolved. Pharmacologic agents such as aminosalicylates, azathioprine/6-mercaptopurine, or steroids are the mainstays of therapy. Newer agents including monoclonal antibodies targeted to specific proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), have emerged and provide great clinical benefit, but unknown long-term toxicity and immunogenicity may limit their use.

Kucharzik T, Maaser C, Lügering A, Kagnoff M, Mayer L, Targan S, Domschke W. · Department of Medicine B, University of Münster, Münster, Germany. · Inflamm Bowel Dis. · Pubmed #17075348 links to  free full text

Abstract: The inflammatory bowel diseases (IBD) are comprised of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC). Research over the last couple of years has led to great advances in understanding the inflammatory bowel diseases and their underlying pathophysiologic mechanisms. From the current understanding, it is likely that chronic inflammation in IBD is due to aggressive cellular immune responses to a subset of luminal bacteria. Susceptibility to disease is thereby determined by genes encoding immune responses which are triggered by environmental stimuli. Based on extensive research over the last decade, there are several new and novel pathways and specific targets on which to focus new therapeutics. The following review summarizes the current view on the four basic tenets of the pathophysiological basis of IBD and its implications for therapies of IBD: genetics, immune dysregulation, barrier dysfunction and the role of the microbial flora.

Kraus TA, Mayer L. · Evanston Northwestern Healthcare Research Institute and Department of Biology, Molecular Biology and Cell Biology, Northwestern University, Illinois, USA. · Curr Opin Gastroenterol. · Pubmed #16220047 No free full text.

Abstract: PURPOSE OF REVIEW: Oral tolerance refers to the ability of the mucosal immune system to actively inhibit systemic immune responses to fed antigens. Recently, clinical trials have used oral tolerance as a therapy for certain chronic inflammatory and autoimmune diseases such as multiple sclerosis and type I diabetes. Inflammatory bowel disease is now widely thought to be caused by the breakdown of oral tolerance through a combination of genetic and environmental factors. Therefore, it seems incongruous that clinicians would try to use oral tolerance therapy to alleviate the symptoms of inflammatory bowel disease. Yet, armed with the results of select animal models, trials have begun for oral tolerance therapy for Crohn's disease. This review will outline the recent advances in understanding oral tolerance, explore the relation between oral tolerance and inflammatory bowel disease, and comment on the likelihood of successful oral tolerance therapy for inflammatory bowel disease. RECENT FINDINGS: The results of an oral tolerance trial in Crohn's disease patients in Israel have shown some promising results, whereas the results of studies of experimentally induced oral tolerance in patients with inflammatory bowel disease from the authors' laboratory have shown that feeding a neoantigen in an attempt to induce oral tolerance is not successful in patients with inflammatory bowel disease. SUMMARY: The fundamental difference in the mechanisms of oral tolerance in mice and humans requires a more focused effort to understand the human mucosal immune system before oral tolerance therapy for autoimmune and chronic inflammatory disorders reaches its full potential.

Ponda PP, Mayer L. · Immunobiology Center, The Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1089, New York, NY 10029, USA. · Curr Mol Med. · Pubmed #16178766 No free full text.

Abstract: The intestinal epithelium has emerged as one of the links between the innate and adaptive immune systems. Novel roles have been elucidated for its participation in antigen uptake and presentation, costimulatory signaling, and intestinal homeostasis. Its concomitant interaction with immune cells and commensal flora demonstrates the epithelium's multifaceted responsibility in protecting against intestinal pathology while maintaining immune competence. Its functional capacity is now more clearly defined in disease states such as celiac disease, Crohn's disease, and ulcerative colitis and in maintaining intestinal integrity through toll-like receptor signaling pathways.

Plevy S, Salzberg B, Van Assche G, Regueiro M, Hommes D, Sandborn W, Hanauer S, Targan S, Mayer L, Mahadevan U, Frankel M, Lowder J. · Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA. · Gastroenterology. · Pubmed #17920064 No free full text.

Abstract: BACKGROUND & AIMS: To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids. METHODS: In this open-label phase 1 study, 32 subjects received visilizumab at a dose of 10 or 15 microg/kg, administered intravenously on 2 consecutive days. Clinical response was defined as a Modified Truelove and Witts Severity Index <10 with a minimum decrease of 3 points; remission was <4 points. Endoscopic remission was a Mayo endoscopic subscore of 0 or 1. RESULTS: Eight patients received 15 microg/kg visilizumab. Because of dose-limiting toxicities (T-cell recovery >30 days in 2 of 8 patients), the dose was reduced to 10 microg/kg in 24 patients. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission, and 44% achieved endoscopic remission. Forty-five percent of patients did not require salvage therapies or colectomy during the first year postdose. Mild to moderate symptoms of cytokine release occurred in 100% and 83% of patients in the 15- and 10-microg/kg dose groups, respectively. All patients exhibited a rapid decrease in circulating CD4(+) T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%). There were no serious infections. CONCLUSIONS: Visilizumab had an acceptable safety profile at the 10-microg/kg dose level and may be clinically beneficial in patients with severe intravenous corticosteroid-refractory ulcerative colitis.

Kraus TA, Toy L, Chan L, Childs J, Cheifetz A, Mayer L. · The Mount Sinai School of Medicine, Immunobiology Center, New York, NY 10029, USA. · Ann N Y Acad Sci. · Pubmed #15681761 No free full text.

Abstract: It has been proposed that defective activation of suppressor or regulatory T cells is one mechanism involved in the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Because suppressor/regulatory T cells are thought to play a role in the promotion of oral tolerance, we attempted to induce oral tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD; n = 12) or ulcerative colitis (UC; n = 13). In the first study, subjects were fed the neoantigen keyhole limpet hemocyanin (KLH) on days 1 to 5 and 11 to 15. Subcutaneous immunization with KLH was performed on day 26, with a booster immunization on day 35. Blood for KLH-induced T cell proliferation and serum for anti-KLH antibody production was obtained at baseline, on day 26 preimmunization (postfed), on day 35 after the first immunization, and again on day 42 after the second immunization. In normal individuals, KLH feeding prior to immunization and booster resulted in reduced KLH-specific T cell proliferation compared with the group that was not fed KLH. However, although on the same KLH-feeding protocol, both CD and UC patients demonstrated significantly enhanced proliferation without oral tolerance induction when compared with baseline values. These data suggest that oral tolerance induction is defective in patients with IBD. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD. Both UC and CD appear to be multigenic disorders with evidence of familial segregation. We analyzed four multiplex Crohn's and two UC families to determine whether the defect in tolerance induction was genetically regulated. In three of the four CD families at least one unaffected family member also failed to tolerate (total 5 of 14 unaffected family members). In the UC families, the defect in tolerance segregated with disease. These data suggest a genetic defect in tolerance induction in Crohn's disease.

Kraus TA, Toy L, Chan L, Childs J, Mayer L. · Immunobiology Center, Mount Sinai School of Medicine, East Building Room 11-20, 1425 Madison Avenue, New York, NY 10029, USA. · Gastroenterology. · Pubmed #15188172 No free full text.

Abstract: BACKGROUND & AIMS: Defective suppressor/regulatory T-cell activation has been proposed as a mechanism to explain the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Previous studies have suggested that inappropriate activation of CD4+ T cells may occur in the gastrointestinal tract in these patients. Because suppressor/regulatory T cells are thought to be one mechanism for the promotion of oral tolerance, we attempted to induce tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD, n = 12) or ulcerative colitis (UC, n = 13). METHODS: Subjects were fed keyhole limpet hemocyanin (KLH) before subcutaneous immunization and booster immunization. Blood for KLH-induced T-cell proliferation and serum for anti-KLH antibody was obtained at baseline and after feeding, immunization, and booster. RESULTS: In the control group, KLH feeding (50 and 250 mg) before immunization and booster resulted in reduced KLH-specific T-cell proliferation compared with the group that was not fed KLH (P < 0.002). However, both CD and UC patients showed significantly enhanced proliferation, without tolerance induction, when compared with baseline values (P < 0.035 and 0.02, respectively). Serum antibody to KLH was present only after immunization in the control group; however, anti-KLH antibody was seen after oral administration in both the UC and CD groups. CONCLUSIONS: Taken together, these data suggest that oral antigen administration does not result in tolerance in CD and UC patients, and might actually result in active immunity. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD.

Sands BE, Tremaine WJ, Sandborn WJ, Rutgeerts PJ, Hanauer SB, Mayer L, Targan SR, Podolsky DK. · Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston 02114, USA. · Inflamm Bowel Dis. · Pubmed #11383595 No free full text.

Abstract: We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Swaminath A, Ullman T, Rosen M, Mayer L, Lichtiger S, Abreu MT. · Division of Digestive and Liver Diseases, Columbia University Presbyterian Hospital, New York, NY 10032, USA. · Aliment Pharmacol Ther. · Pubmed #19006540 No free full text.

Abstract: BACKGROUND: Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohn's disease (CD) and for patients with loss of response to infliximab. AIM: To evaluate the indications for adalimumab, the proportion of inflammatory bowel disease patients who require dose escalation and to identify whether this strategy is effective in inducing or maintaining remission. METHODS: Patients prescribed adalimumab for CD were identified and included for analysis, if they had follow-up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. Clinical judgment was used to determine severity of disease. A second GI physician confirmed disease severity as determined by the first physician. RESULTS: A total of 48 out of 60 patients met inclusion criteria. Adalimumab was used to treat CD in 47/48 (98%) and ulcerative colitis in one (2%). Most patients had moderate 30/48 (63%) or severe 17/48 (35%) disease. Prior infliximab exposure was present in 42/48 (88%). Adalimumab dose escalation occurred in 14/48 (29%) within an average time of 2.2 months (s.d. 1.5 months). A majority of patients who required dose escalation, nine of 14 (64%) did not improve clinically. Steroids could be discontinued in three of 16 (18.8%). Clinical improvement was noted in 21/48 (43.8%) and one of 48 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in four of 48 (8%) of patients. CONCLUSIONS: This retrospective review from a single academic medical centre suggests that a minority of patients, who cannot be maintained on 40 mg every other week, of adalimumab benefit from an increased dose. This suggests the need for a treatment with an alternative mode of action in anti-TNF failures.

Marion JF, Waye JD, Present DH, Israel Y, Bodian C, Harpaz N, Chapman M, Itzkowitz S, Steinlauf AF, Abreu MT, Ullman TA, Aisenberg J, Mayer L, Anonymous00103. · Mount Sinai School of Medicine, New York, New York 10028-0517, USA. · Am J Gastroenterol. · Pubmed #18844620 No free full text.

Abstract: OBJECTIVES: Patients with extensive, longstanding chronic ulcerative or Crohn's colitis face greater risks of developing colorectal cancer. Current standard surveillance relies on detecting dysplasia using random sampling at colonoscopy but may fail to detect dysplasia in many patients. Dye spraying techniques have been reported to aid in detecting otherwise subtle mucosal abnormalities in the setting of colitis. We prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia. METHODS: One hundred fifteen patients were referred to the Chromoendoscopy Study Group and prospectively screened for the study. One hundred two (64 M, 38 F) (79 UC 23 CC) patients meeting the inclusion criteria were enrolled. Following a standard bowel preparation, each patient was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with four random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied. Each patient had a single examination, which included two passes of the colonoscope. Specimens were reviewed in a blinded fashion by a single gastrointestinal pathologist. The three methods were then compared with each patient serving as his or her own control. RESULTS: Targeted biopsies with dye spray revealed significantly more dysplasia (16 patients with low grade and 1 patient with high grade) than random biopsies (3 patients with low-grade dysplasia) (P= 0.001) and more than targeted nondye spray (8 patients with low-grade and 1 patient with high-grade dysplasia) (P= 0.057). Targeted biopsies with and without dye spray detected dysplasia in 20 patients compared with 3 using Method (a) (P= 0.0002, two-tailed exact McNemar's Test). There were no adverse events. CONCLUSIONS: Colonoscopic surveillance of chronic colitis patients using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods. Accordingly, this technique warrants incorporation into clinical practice in this setting and consideration as a standard of care for these patients. The value of multiple random biopsies as a surveillance technique should be revisited.

Dahan S, Roda G, Pinn D, Roth-Walter F, Kamalu O, Martin AP, Mayer L. · Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA. · Gastroenterology. · Pubmed #18045591 No free full text.

Abstract: BACKGROUND & AIMS: Intestinal lymphoepithelial interactions occur in the epithelium and the subepithelial space. We asked whether normal, Crohn's disease (CD), or ulcerative colitis (UC) lamina propria lymphocytes (LPL) could promote intestinal epithelial cell (IEC) growth and differentiation. METHODS: T84 cells were cocultured with isolated LPL. IECs were then lysed and subjected to measurement of intestinal alkaline phosphatase (IAP) activity; Western blot analysis for MAPK and Akt activation; and real-time polymerase chain reaction to assess caudal-related homeoprotein 2 (CDX2) messenger RNA (mRNA) levels. Tissue sections were immunostained for evidence of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) activation, CDX2, and IAP; and CDX2 mRNA expression was assessed in human colonic biopsy specimens. RESULTS: IAP activity was increased in T84 cells cocultured for 8 days with normal LPL (P < .05) and even greater with CD LPL (P < .001). Crypt IECs in active CD mucosa expressed IAP ex vivo. Phospho-MAPK (extracellular signal-regulated kinase 1/2, p38, and c-Jun-N-terminal kinase) and phospho-Akt were seen as early as 30 minutes after coculture. MAPK activation was greatest in T84 cells cocultured with CD LPL. There was a specific increase in Phospho-p38 MAPK and Phospho-Akt staining in the nuclei of crypt IECs in active vs inactive CD, normal mucosa, and UC mucosa. CDX2 mRNA expression was increased in CD LPL cocultured T84 cells, which did not correlate with CDX2 protein localization ex vivo. CONCLUSIONS: There is cross talk between LPL and IECs, which leads to IEC differentiation. The differentiation is accelerated in CD mucosa.

Nanni P, Parisi D, Roda G, Casale M, Belluzzi A, Roda E, Mayer L, Roda A. · Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, Bologna, Italy. · Rapid Commun Mass Spectrom. · Pubmed #18022963 No free full text.

Abstract: The identification of new biomarkers or a disease-related protein fingerprint for inflammatory bowel diseases (IBDs) represents a major task in the diagnosis, prognosis and pharmacological therapy. To address these issues, a simple and rapid analytical proteomic method for serum protein profiling based on selective beads-based solid-phase bulk extraction, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and chemometric data analysis was developed. Serum proteins from healthy subjects (22) and patients with Crohn's disease (15) and ulcerative colitis (26) were selectively extracted according to reversed-phase (C18), strong anion-exchange (SAX) and metal ion affinity (IDA-Cu(II)) principles. This approach allowed enrichment of serum proteins/peptides due to the high interaction surface between analytes and the solid phase and high recovery due to the elution step performed directly on the MALDI-target plate. The MALDI-TOF MS serum protein profiles were acquired and, after a data pre-processing step, analyzed by linear discriminant analysis (LDA), a chemometric classification technique, in order to classify serum samples among healthy subjects and patients with inflammatory bowel diseases (IBDs). Since the high number of variables in the MALDI spectra (more than 16000 m/z values) prevents the use of LDA, the variables were reduced to 10-20 by features selection, thus allowing the evaluation of a pattern of m/z values with high discriminant power. Serum protein profiles obtained by reversed-phase extraction and the selection of 20 m/z values gave the best overall prediction ability (96.9%). The recognition of these m/z values may allow the identification of protein biomarkers involved in IBDs.

Allez M, Tieng V, Nakazawa A, Treton X, Pacault V, Dulphy N, Caillat-Zucman S, Paul P, Gornet JM, Douay C, Ravet S, Tamouza R, Charron D, Lémann M, Mayer L, Toubert A. · Service de Gastroentérologie, Hôpital Saint-Louis, Paris, France; INSERM Unité 662, Hôpital Saint-Louis, Paris, France. · Gastroenterology. · Pubmed #17570210 No free full text.

Abstract: BACKGROUND & AIMS: Crohn's disease (CD) is an inflammatory bowel disease characterized by uncontrolled immune responses to bacterial flora, with excessive activation of T lymphocytes. MICA is a stress-induced major histocompatibility complex-related molecule expressed on normal intestinal epithelial cells (IECs) and recognized by the NKG2D-activating receptor on CD8(+) T cells, gammadelta T cells, and natural killer cells. We examined the role of MICA-NKG2D interactions in the activation of T lymphocytes in CD. METHODS: MICA expression was analyzed by flow cytometry on IECs isolated from patients with active inflammatory bowel disease and controls. NKG2D expression and function were analyzed on lamina propria and peripheral blood lymphocytes. RESULTS: MICA expression was significantly increased on IECs in CD, with higher expression in macroscopically involved areas. A subset of CD4(+) T cells expressing NKG2D was increased in the lamina propria from patients with CD compared with controls and patients with ulcerative colitis. CD4(+)NKG2D(+) T cells with a Th1 cytokine profile and expressing perforin were increased in the periphery and in the mucosa in CD. CD4(+)NKG2D(+) T-cell clones were functionally active through MICA-NKG2D interactions, producing interferon-gamma and killing targets expressing MICA. IECs from patients with CD had the ability to expand this subset in vitro. CD4(+)NKG2D(+) lamina propria lymphocytes from patients with CD highly expressed interleukin-15R alpha, and interleukin-15 increased NKG2D and DAP10 expression in CD4(+)NKG2D(+) T-cell clones. CONCLUSIONS: These findings highlight the role of MICA-NKG2D in the activation of a unique subset of CD4(+) T cells with inflammatory and cytotoxic properties in CD.

Dotan I, Allez M, Nakazawa A, Brimnes J, Schulder-Katz M, Mayer L. · IBD Service, Dept. of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. · Am J Physiol Gastrointest Liver Physiol. · Pubmed #17347451 links to  free full text

Abstract: Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-gamma, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-gamma indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

Perera L, Shao L, Patel A, Evans K, Meresse B, Blumberg R, Geraghty D, Groh V, Spies T, Jabri B, Mayer L. · Immunobiology Center, Mount Sinai Medical Center, New York, New York 10029, USA. · Inflamm Bowel Dis. · Pubmed #17238179 links to  free full text

Abstract: It is well recognized that the nature of the immune response is different in the intestinal tract than in peripheral lymphoid organs. The immunologic tone of the gut-associated lymphoid tissue is one of suppression rather than active immunity, distinguishing pathogens from normal flora. Failure to control mucosal immune responses may lead to inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC) and celiac disease. It has been suggested that this normally immunosuppressed state may relate to unique antigen-presenting cells and unique T-cell populations. The intestinal epithelial cell (IEC) has been proposed to act as a nonprofessional antigen-presenting cell (APC). Previous studies have suggested that antigens presented by IECs result in the activation a CD8(+) regulatory T-cell subset in a nonclassical MHC I molecule restricted manner. We therefore analyzed the expression of nonclassical MHC I molecules by normal IECs and compared this to those expressed by inflammatory bowel disease (IBD) IECs. Normal surface IEC from the colon and, to a much lesser extent, the small bowel express nonclassical MHC I molecules on their surface. In contrast, mRNA is expressed in all intestinal epithelial cells. Surface IEC express CD1d, MICA/B, and HLA-E protein. In contrast, crypt IECs express less or no nonclassical MHC I molecules but do express mRNA for these molecules. Furthermore, the regulation of expression of distinct nonclassical class I molecules is different depending on the molecule analyzed. Interestingly, IECs derived from patients with UC fail to express any nonclassical MHC I molecules (protein and HLA-E mRNA). IECs from CD patients express HLA-E and MICA/B comparable to that seen in normal controls but fail to express CD1d. Thus, in UC there may be a failure to activate any nonclassical MHC I molecule restricted regulatory T cells that may result in unopposed active inflammatory responses. In CD only the CD1d-regulated T cells would be affected.

Kraus TA, Cheifetz A, Toy L, Meddings JB, Mayer L. · Mount Sinai School of Medicine Immunobiology Center, New York, New York 10029, USA, and the Gastrointestinal Research Group, University of Calgary Health Sciences Centre, Calgary, Alberta, Canada. · Inflamm Bowel Dis. · Pubmed #16432371 links to  free full text

Abstract: BACKGROUND: Previous studies have suggested that there may be a defect in the control of immune responses locally in the intestines of patients with inflammatory bowel disease (IBD). Recently, we documented a failure to induce oral tolerance to a fed soluble protein antigen, keyhole limpet hemocyanin (KLH), in IBD patients. Both Crohn's disease (CD) and ulcerative colitis (UC) appear to be multigenic disorders with evidence of familial segregation. In this study, we analyzed multiplex IBD families to determine whether the defect in oral tolerance induction is genetically regulated. METHODS: Patients and first-degree relatives from 6 multiplex families were fed KLH 50 mg on days 0 to 5 and 10 to 15, followed by subcutaneous immunizations on days 26 and 35. Blood was obtained and analyzed for KLH-specific T cell proliferative responses and cytokine production. Intestinal permeability was also assessed. RESULTS: In contrast to normal controls, all IBD patients, save 1 (10 patients out of 11 tested P<.0001 versus normal controls), failed to develop oral tolerance to KLH. Furthermore, in 3 of the 4 CD families, at least 1 unaffected family member (total of 5/14 unaffected individuals, P=.002 versus normal controls) also failed to tolerize. This is in sharp contrast to unaffected individuals with no family history of IBD (1/31 tested to date). CONCLUSIONS: This failure of tolerance induction could not be attributed to increased intestinal permeability. In the UC families, the defect in tolerance segregated with disease. These data support a genetic defect in tolerance induction in CD.

Brimnes J, Allez M, Dotan I, Shao L, Nakazawa A, Mayer L. · Immunobiology Center, Mount Sinai Medical Center, New York, NY 10029, USA. · J Immunol. · Pubmed #15843585 links to  free full text

Abstract: Mucosal tolerance is believed to be partly mediated by regulatory T cells. Intestinal epithelial cells (IECs) may play an important role in the generation of such regulatory cells, because they are able to process and present Ag to T cells. Furthermore, we have previously demonstrated that IECs are able to generate regulatory CD8(+) T cells in vitro. In the present study, we have analyzed lamina propria (LP) lymphocytes for the presence of such regulatory CD8(+) T cells in normal individuals as well as in patients with inflammatory bowel disease (IBD). The results of the present study show that LP CD8(+) T cells derived from normal controls possess regulatory activity, whereas both unfractionated LP lymphocytes and purified LP CD4(+) T cells do not. The LP CD8(+) T cells suppress Ig production by pokeweed mitogen-stimulated PBMCs by 31-80%, in a cell contact-dependent manner. No significant difference in suppression between CD28(+) and CD28(-)CD8(+) LP T cells was observed. In contrast to CD8(+) T cells from normal LP, CD8(+) T cells isolated from LP of IBD patients, did not suppress Ig production by pokeweed mitogen-stimulated PBMC (five of six ulcerative colitis specimens; six of six Crohn's disease specimens). Furthermore, we demonstrate that the frequency of TCR Vbeta5.1-positive CD8(+) T cells, which we previously have demonstrated to be regulatory and to be expanded by IECs in vitro, is decreased in IBD LP compared with normal LP. In conclusion, this study demonstrates that CD8(+) T cells with regulatory activity are present in the LP of normal healthy individuals, but not in patients with IBD, suggesting that these cells might play an active role in mucosal tolerance.

Lahav M, Levite M, Bassani L, Lang A, Fidder H, Tal R, Bar-Meir S, Mayer L, Chowers Y. · Department of Gastroenterology, Chaim Sheba Medical Center, Tel Hashomer, Israel. · Clin Exp Immunol. · Pubmed #11876744 links to  free full text

Abstract: Lidocaine and related local anaesthetics have been shown to be effective in the treatment of ulcerative colitis (UC). However, the mechanisms underlying their therapeutic effect are poorly defined. Intestinal epithelial cells play an important role in the mucosal inflammatory response that leads to tissue damage in UC via the secretion of pro-inflammatory cytokines and chemokines. The aim of this study was to evaluate the direct immunoregulatory effect of lidocaine on pro-inflammatory cytokine and chemokine secretion from intestinal epithelial cells. HT-29 and Caco-2 cell lines were used as a model system and treated with lidocaine and related drugs. The expression of IL-8, IL-1beta and the IL-1 receptor antagonist (RA) were assessed by ELISA and quantification of mRNA. In further experiments, the effect of lidocaine on the secretion of IL-8 from freshly isolated epithelial cells stimulated with TNFalpha was tested. Lidocaine, in therapeutic concentrations, inhibited the spontaneous and TNFalpha-stimulated secretion of IL-8 and IL-1beta from HT-29 and Caco-2 cell lines in a dose-dependent manner. Similarly, suppression of IL-8 secretion was noted in the freshly isolated epithelial cells. Other local anaesthetics, bupivacaine and amethocaine, had comparable effects. Lidocaine stimulated the secretion of the anti-inflammatory molecule IL-1 RA. Both the inhibitory and the stimulatory effects of lidocaine involved regulation of transcription. The results imply that the therapeutic effect of lidocaine may be mediated, at least in part, by its direct effects on epithelial cells to inhibit the secretion of proinflammatory molecules on one hand while triggering the secretion of anti-inflammatory mediators on the other.

Mayer L. · Immunobiology Center, Box 1089, Mount Sinai School of Medicine, One East 100th Street, New York, NY 10029, USA. · Mt Sinai J Med. · Pubmed #10828906 links to  free full text

Abstract: An evolution in our understanding of the inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease, correlates with increased knowledge of the function of the mucosal immune system. In the early 1960s and 1970s, IBD was considered to be an autoimmune disease in which there was a directed attack by humoral and cellular elements of the immune system against intestinal tissues. These studies did not withstand the test of time, and from the 1970s through the 1990s there was a growing appreciation that defects in cellular immunity, not auto-reactive in nature, played a larger role in disease pathogenesis. Research at Mount Sinai focused in on these cellular T cell defects and helped pave the way for the current model of disease pathogenesis.