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Biomedical subjects

Maria T Abreu

Publications and source records attributed to Maria T Abreu.

At least 19 recordsLinked to original sources
PubMed2006

Advances in the pathogenesis of inflammatory bowel disease.

Most people do not develop inflammatory bowel disease (IBD) in spite of the density of the commensal flora. In the past few years, several areas of gut mucosal immunology have emerged that will permit advances in the management of IBD at the bedside. The commensal flora is only beginning to be fully appreciated as another metabolic organ in the body. Innate immunity as it relates to the gut has complemented our understanding of the adaptive immune response. The most important susceptibility gene described for Crohn's disease, the NOD2 gene, participates in the innate immune response to pathogens. Patients carrying NOD2 mutations have an increased adaptive immune response to commensal organisms as measured by higher titers of antimicrobial antibodies, such as anti-CBir and anti-Saccharomyces cerevisiae antibodies. Toll-like receptors expressed by antigen-presenting cells (APCs) in the gut and intestinal epithelial cells also play a role in recognition of intestinal flora. Within the APC category, dendritic cells link the innate and adaptive immune systems and shape the nature of the adaptive immune response to commensal bacteria. With respect to adaptive immunity, a new signaling pathway involving a distinct helper CD4 T-cell subset producing interleukin-17 may become a target for the treatment of chronic inflammatory diseases. This review focuses on developments likely to culminate in advances in patient care.

Animals↗
PubMed2006

Use of capsule endoscopy for established Crohn's disease.

There remains significant uncertainty regarding the role of capsule endoscopy in the setting of known inflammatory bowel disease (IBD). Capsule endoscopy should be considered for patients who have indeterminate colitis, who are failing medical therapy or who may require colectomy, who have truly unexplained symptoms based on standard endoscopy and radiography, and who have IBD and obscure bleeding. Although capsule endoscopy clearly detects small bowel pathology with greater sensitivity than other methods, the implications of these lesions are not fully understood. At this time, use of capsule endoscopy as a tool for the evaluation of mucosal healing or for prognostication of post-operative recurrence remains investigational.

Crohn Disease↗
PubMed2006

Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine.

BACKGROUND & AIMS: We recently showed that mice deficient in Toll-like receptor 4 (TLR4) or its adapter molecule MyD88 have increased signs of colitis compared with wild-type (WT) mice after dextran sodium sulfate (DSS)-induced injury. We wished to test the hypothesis that cyclooxygenase 2 (Cox-2)-derived prostaglandin E2 (PGE2) is important in TLR4-related mucosal repair. METHODS: Cox-2 expression was analyzed by real-time polymerase chain reaction, immunohistochemistry, Western blotting, and luciferase reporter constructs. Small interfering RNA was used to inhibit expression of MyD88. TLR4-/- or WT mice were given 2.5% DSS for 7 days. Proliferation and apoptosis were assessed using bromodeoxyuridine staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays, respectively. PGE2 was given orally to DSS-treated mice. RESULTS: Intestinal epithelial cell lines up-regulated Cox-2 expression in a TLR4- and MyD88-dependent fashion. Lipopolysaccharide-mediated stimulation of PGE2 production was blocked by a selective Cox-2 inhibitor or small interfering RNA against MyD88. After DSS injury, Cox-2 expression increased only in WT mice. TLR4-/- mice have significantly reduced proliferation and increased apoptosis after DSS injury compared with WT mice. PGE2 supplementation of TLR4-/- mice resulted in improvement in clinical signs of colitis and restoration of proliferation and apoptosis to WT values. The mechanism for improved epithelial repair may be through PGE2-dependent activation of the epidermal growth factor receptor. CONCLUSIONS: We describe an important link between TLR4 signaling and Cox-2 expression in the gut. TLR4 and MyD88 signaling are required for optimal proliferation and protection against apoptosis in the injured intestine. Although TLR4 signaling is beneficial in the short term, chronic signaling through TLR4 may lower the threshold for colitis-associated cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Treatment with infliximab is associated with increased markers of bone formation in patients with Crohn's disease.

OBJECTIVE: Osteoporosis is a common complication of Crohn's disease (CD). Glucocorticoid use and detrimental effects of inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha) can lead to osteoporosis. The aim of this study was to assess the ability of treatment with the TNF-alpha antagonist infliximab to increase bone formation as measured by surrogate markers of bone turnover in patients with active CD. METHODS: Sera from 38 prospectively enrolled CD patients were examined for levels of bone alkaline phosphatase (BAP), N-telopeptide of type I collagen (NTX), immunoreactive parathyroid hormone (iPTH), calcium, and pro-inflammatory cytokines at baseline and 4 weeks following infliximab infusion. Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and glucocorticoid dose also were collected. RESULTS: In this cohort, CDAI and IBDQ scores were significantly improved at week 4 (P<0.001). Infliximab therapy was associated with an increase in BAP, a marker of bone formation (P=0.010), whereas NTX, a marker of bone resorption, was not increased (P=0.801). Among 22 patients who were taking glucocorticoids, mean glucocorticoid dose decreased 36% (P<0.001; -7.9 mg). CONCLUSIONS: Treatment with infliximab was associated with increased markers of bone formation (BAP) without increasing bone resorption (NTX). This effect may be due to a beneficial effect of TNF-alpha blockade on bone turnover, a beneficial effect on CD activity resulting in decreased glucocorticoid dose, or both. Studies of longer duration are needed to assess the effect of infliximab on bone mineral density.

Adolescent↗
PubMed2006

Antibodies to I2 predict clinical response to fecal diversion in Crohn's disease.

OBJECTIVES: Fecal diversion is occasionally indicated in patients with advanced perianal or colorectal Crohn's disease (CD). Because CD may result from an aberrant immunologic response to bacteria within the gut lumen, fecal diversion should be effective in managing these complications. However, not all patients achieve a clinical response after fecal diversion. CD patients can be characterized by their antibody responses against Pseudomonas fluorescens (I2), E.coli outer membrane porin C (OmpC), oligomannan (anti-Saccharomyces cerevisiae antibodies [ASCA]), and antinuclear antigens (perinuclear antineutrophil cytoplasmic antibodies [pANCA]). This study examines the association between clinical features and seroreactivity to these microbial and auto-antigens in predicting a clinical response to fecal diversion. METHODS: Twenty-seven consecutive CD patients undergoing fecal diversion were included. Sera were drawn and tested for anti-I2, anti-OmpC, ASCA, and pANCA in a blinded fashion. Response was assessed using clinical parameters. RESULTS: Seventeen (63%) patients underwent fecal diversion for medically resistant proctocolitis and 10 (37%) for severe perianal disease. Median follow-up was 41 months. Seventeen (63%) patients achieved a clinical response. No preoperative clinical or surgical factor predicted response to diversion. Clinical response after fecal diversion was seen in 15 of 16 (94%) patients who were I2 positive compared with only 2 of 11 (18%) patients who were I2 negative (P = 0.0001). Seroreactivity to OmpC, ASCA, or pANCA was not associated with a clinical response to diversion. CONCLUSION: Expression of I2 antibodies against a bacterial antigen of Pseudomonas fluorescens was highly associated with clinical response to fecal diversion in CD patients.

Adult↗
PubMed2005

TLR signaling in the gut in health and disease.

The human intestine has evolved in the presence of diverse enteric microflora. TLRs convert the recognition of pathogen-associated molecules in the gut into signals for anti-microbial peptide expression, barrier fortification, and proliferation of epithelial cells. Healing of injured intestinal epithelium and clearance of intramucosal bacteria require the presence of intact TLR signaling. Nucleotide oligomerization domain (Nod)1 and Nod2 are additional pattern recognition receptors that are required for defense against invasive enteric pathogens. Through spatial and functional localization of TLR and Nod molecules, the normal gut maintains a state of controlled inflammation. By contrast, patients with inflammatory bowel disease demonstrate inflammation in response to the normal flora. A subset of these patients carry polymorphisms in TLR and CARD15/NOD2 genes. A better understanding of the delicate regulation of TLR and Nod molecules in the gut may lead to improved treatment for enteric infections and idiopathic inflammatory bowel diseases.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Design issues and outcomes in IBD clinical trials.

Successful clinical trials in inflammatory bowel disease are based on precise definitions of study populations, standardized and well-defined interventions, reliable indices of disease activity, and clearly stipulated outcome measures. Interpretation of research results is often complicated by the differentiation of goals of therapy (remission induction and maintenance, quality of life) and the multitude of patient subsets. Choosing the correct patient subtype to enroll in a clinical trial is critical to the results of a study, its conclusions, and its applicability to the clinical setting. Validated, easy-to-use disease activity indices allow interpretation of results across trials. The use of biomarkers as surrogate clinical endpoints provides reproducibility, ease of statistical handling as a continuous variable, and consistent measurement of response to treatment. Despite these potential advantages, biomarkers of disease activity lack specificity and will need to be validated against clinically meaningful outcomes. Careful subject selection, standardization of disease activity indices, and precise outcome measurement are the keys to continued improvement of the inflammatory bowel disease research process.

Biomarkers↗
PubMed2005

Defects in mucosal immunity leading to Crohn's disease.

Crohn's disease (CD) is characterized by patchy transmural inflammation involving any part of the intestinal tract. Animal models have provided a great deal of insight into the pathogenesis of CD, but no animal model has recapitulated the full spectrum of manifestations witnessed in human disease. The defects in mucosal immunity in CD can be divided into those that involve the epithelial barrier, those that involve the innate immune response, and finally, defects in the adaptive immune response. Defects in the epithelial barrier in CD include an increase in intestinal permeability, increased adherence of bacteria, and decreased expression of defensins. Murine and human studies have demonstrated an increased expression of T-helper 1 (Th1) cytokines by lamina propria lymphocytes. This increased Th1 cytokine expression is driven by interleukin-12 (IL-12)/IL-23 and tumor necrosis factor-like 1A (TL1A) production by antigen-presenting cells, resulting in Tbet expression by CD4+ T cells. Another dimension of the inappropriate immune response in CD is T-cell and B-cell reactivity to luminal microbes. With the identification of the nucleotide-binding oligomerization domain 2 (NOD2) gene as a susceptibility gene, defects in the innate immune response are beginning to be explored. One may consider a model in which defective innate immune clearance of pathogens or commensal bacteria in CD leads to an inappropriate adaptive immune response to the commensal flora.

Animals↗
PubMed2005

Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab.

OBJECTIVES: Although infliximab is highly effective in the treatment of Crohn's disease (CD), attenuated response to infliximab may develop over time in a subgroup of patients. The aim of our study was to examine the safety and efficacy of adalimumab (D2E7), a fully humanized anti-TNF-alpha Ab, in CD patients who had experienced an attenuated response to infliximab. METHODS: Fifteen patients with active CD who experienced an attenuated response to infliximab were treated with adalimumab over a 6-month period. Patients, received a loading dose of 80 mg subcutaneously followed by 40 mg every 2 wk. The clinical response to adalimumab was classified as complete response, partial response, or nonresponse. RESULTS: Two patients received the loading dose of adalimumab but did not have adequate follow-up evaluations. Of the remaining 13 patients, 7 (54%) had a complete response, 4 (31%) had a partial response, and 2 (15%) were nonresponders. In six patients, the maintenance dose was increased in order to maintain clinical response. Eight of 11 (73%) patients on concurrent corticosteroids were able to discontinue or significantly decrease the dose of the steroids. Adalimumab was well tolerated without signs or symptoms of allergic reaction except in two patients who developed an injection site reaction. CONCLUSIONS: Our preliminary data suggest that adalimumab may be a safe and effective therapy for patients with CD who have experienced an attenuated response to infliximab.

Adalimumab↗
PubMed2005

Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis.

Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4-/- and MyD88-/- mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4-/- mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4-/- mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88-/- mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4-/- and MyD88-/- mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4-/- and MyD88-/- mice. The similarity in crypt epithelial damage between TLR4-/- or MyD88-/- and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Antibodies to tumor necrosis factor-alpha in the treatment of Crohn's disease.

Crohn's disease is characterized by acute and chronic intestinal inflammation, and can involve any part of the gastrointestinal tract. The most frequently involved areas of the intestine (the terminal ileum and colon) have higher bacterial loads than the rest of the intestine, suggesting a role for a dysregulated immune response to luminal bacteria. Research into the pathogenesis of Crohn's disease using animal models supports a role for Th1-mediated immune responses, and inhibition of the generation of a Th1 response is known to prevent disease. Based on these observations, antitumor necrosis factor-alpha (anti-TNFalpha) therapies have been used to treat patients with Crohn's disease and more recently with ulcerative colitis. Certain anti-TNFalpha therapies, such as infliximab, have resulted in dramatic clinical responses in patients with Crohn's disease. Other therapies such as etanercept, however, have not been effective. In this review we will discuss the different strategies that have been employed to inhibit TNFalpha and their relative merits. We will also address factors that predict response to therapy such as concurrent immunomodulators, high C-reactive protein expression, and polymorphisms in the Fcgamma receptor.

Animals↗
PubMed2005

Ulcerative colitis therapy: importance of delivery mechanisms.

Since the initial observation that mesalamine or 5-aminosalicylate (5-ASA) has an anti-inflammatory effect on ulcerative colitis, investigators have been trying to improve on the delivery mechanisms of this compound. As it is believed that the anti-inflammatory effect of 5-ASAs is mediated topically, current formulations are designed to release 5-ASA in the small intestine and colon, or predominantly in the colon. A dose-response curve is seen with some preparations of mesalamine but not all. In general, 5-ASAs are effective in patients with ulcerative colitis and much less effective in Crohn's disease. Evidence demonstrates that 5-ASAs are effective for induction of remission and maintenance of remission. Preparations that deliver 5-ASA in a pH-dependent manner are most affected by variability in luminal pH, whereas those that depend on bacterial cleavage for release of the active 5-ASA are most affected by transit time. Most studies have not compared different preparations of mesalamine and examined differences in colonic delivery. Depending on the endpoint examined in the studies, efficacy of the various 5-ASA products appears similar at the most optimal doses. For a given patient, however, it may be necessary to experiment with more than one preparation if an initial trial results in a suboptimal response.

Aminosalicylic Acids↗
PubMed2004

Beta-defensin-2 expression is regulated by TLR signaling in intestinal epithelial cells.

The intestinal epithelium serves as a barrier to the intestinal flora. In response to pathogens, intestinal epithelial cells (IEC) secrete proinflammatory cytokines. To aid in defense against bacteria, IEC also secrete antimicrobial peptides, termed defensins. The aim of our studies was to understand the role of TLR signaling in regulation of beta-defensin expression by IEC. The effect of LPS and peptidoglycan on beta-defensin-2 expression was examined in IEC lines constitutively or transgenically expressing TLRs. Regulation of beta-defensin-2 was assessed using promoter-reporter constructs of the human beta-defensin-2 gene. LPS and peptidoglycan stimulated beta-defensin-2 promoter activation in a TLR4- and TLR2-dependent manner, respectively. A mutation in the NF-kappaB or AP-1 site within the beta-defensin-2 promoter abrogated this response. In addition, inhibition of Jun kinase prevents up-regulation of beta-defensin-2 protein expression in response to LPS. IEC respond to pathogen-associated molecular patterns with expression of the antimicrobial peptide beta-defensin-2. This mechanism may protect the intestinal epithelium from pathogen invasion and from potential invaders among the commensal flora.

Animals↗
PubMed2004

New insights into the pathogenesis of inflammatory bowel disease.

Several important advances have been made over the past few years that have expanded our knowledge of the immunology of the gut and its complex interactions with commensal organisms. Critical developments in our understanding of the pathogenesis of inflammatory bowel diseases include the discovery of Toll-like receptors and the identification of not one but two susceptibility genes for Crohn's disease. We have furthered our understanding significantly concerning the role of dendritic cells in the development of gut inflammation. In addition, a novel hypothesis suggesting a protective role for helminthic infections is gaining experimental evidence and direct clinical applicability. In this review we summarize these key developments in the pathophysiology of inflammatory bowel disease and attempt to ascribe clinical relevance where applicable.

Dendritic Cells↗