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Maria T Abreu

Publications and source records attributed to Maria T Abreu.

35 records · Page 2Linked to original sources
PubMed2004

Innate immunity and toll-like receptors: clinical implications of basic science research.

Humans are constantly exposed to a wide variety of microorganisms that can cause infection. In self-defense, the human host has evolved complex protective mechanisms, and Toll-like receptors (TLRs) have emerged as a central point in defense. These receptors bind molecular structures that are expressed by microbes but are not expressed by the human host, eg, lipopolysaccharides (LPS) or double-stranded RNA (dsRNA). Activation of these receptors initiates an inflammatory cascade that attempts to clear the offending pathogen and set in motion a specific adaptive immune response. Defects in sensing of pathogens may predispose the host to recurrent infections. The relative rarity of these syndromes of defective innate immunity, however, speaks to the redundancy in sensing of pathogens by the innate immune system. More common, polymorphisms in TLR4 are associated with increased predisposition to severe and recurrent infections but protection against atherosclerotic disease due to diminished inflammation. Toll-like receptor signaling may also contribute to the pathophysiology of disease and injure the host by activating a deleterious immune response such as in sepsis or inflammatory bowel disease (IBD). The focus of this article is to describe the role of TLRs in the innate immune response in health and disease.

Humans↗
PubMed2004

Biomarkers in inflammatory bowel disease.

PURPOSE OF REVIEW: Inflammatory bowel disease is characterized by chronic intestinal inflammation in the absence of a recognized pathogen. In its classic description, there are two principal forms of inflammatory bowel disease: Crohn disease and ulcerative colitis. The clinical heterogeneity of these disorders alludes to the possibility of diverse pathogenetic mechanisms underlying inflammatory bowel diseases. The purpose of this review is to summarize the latest information on biomarkers of Crohn disease and ulcerative colitis. RECENT FINDINGS: The authors have focused on serologic markers for which emerging data support their use as predictors of disease evolution. Serologic markers such as perinuclear antineutrophil cytoplasmic antibody, anti-Saccharomyces cerevisiae antibody, anti-OmpC, and anti-I2 may be useful in distinguishing inflammatory bowel diseases from functional disorders and ulcerative colitis from Crohn disease and predicting complications of disease. Genetic markers such as CARD15/NOD2 may be useful in the future when combined with other markers to predict disease course. Biochemical markers of inflammation such as C-reactive protein are useful to stratify patients likely to respond to biologic therapies and to follow response to treatment. In the future, functional genomics and proteomics will be used to rapidly screen patients for subclinical characteristics that can predict disease course and response to therapy. SUMMARY: A variety of biomarkers can be used to stratify patients with inflammatory bowel disease into more homogeneous subgroups with respect to response to therapy and disease progression.

Journal Article↗
PubMed2004

A pilot study of adalimumab in infliximab-allergic patients.

The anti-TNF-alpha antibody infliximab (Remicade) is highly effective in the treatment of Crohn's disease. A subset of patients experience allergic reactions as a result of antibodies to infliximab (ATIs). The purpose of the current study is to describe the safety and efficacy of adalimumab (Humira) in patients previously allergic or intolerant to infliximab. Adalimumab is an anti-TNF-alpha agent containing only human peptide sequences. Seven patients have been treated with adalimumab who had experienced immediate- or delayed-hypersensitivity reactions to infliximab and one with infliximab-induced lupus. Except for injection site discomfort, adalimumab was well tolerated without signs or symptoms of allergic reactions. One patient who had previously received pooled human immunoglobulin developed a pruritic rash after each dose of adalimumab. Patients with active disease who had previously experienced a robust response to infliximab responded to adalimumab as reflected by an improvement in Harvey-Bradshaw index and inflammatory markers. Based on these preliminary data, adalimumab may be a safe and effective substitute for infliximab-allergic patients. Individuals who have been exposed to human antibodies may be sensitized to other human antibodies such as adalimumab.

Adalimumab↗
PubMed2004

The spectrum of gastrointestinal toxicity and effect on disease activity of selective cyclooxygenase-2 inhibitors in patients with inflammatory bowel disease.

The safety and toxicity associated with the use of selective cyclooxygenase-2 (COX-2) inhibitors in patients with inflammatory bowel disease (IBD) has not been extensively studied. Thirty-three patients with IBD who were prescribed celecoxib or rofecoxib were identified from questionnaire during their clinic visit at the Cedars-Sinai IBD Center between 1999 and 2002. Twenty-six had Crohn's disease (CD), 6 had ulcerative colitis (UC), and 1 had indeterminate colitis (IC). Twenty-one received rofecoxib, 10 celecoxib, and 2 received both medications at different time points. Overall, 13 (39%) patients experienced disease exacerbation, 7 of which had received celecoxib and six rofecoxib. IBD exacerbation associated with COX-2 treatment did not correlate with age, disease activity, or use of immunosuppressive medications. All patients experienced flare-up of their underlying IBD within 6 weeks of initiating COX-2 therapy. Five of 13 (38%) patients had resolution of their symptoms after discontinuing the COX-2 inhibitor, but the remaining patients required additional medical therapy to control their disease. Six other patients (18%) experienced GI side effects not associated with their underlying IBD. Five developed abdominal pain, and one developed a duodenal ulcer and a circumferential ileo-colonic ulceration with GI bleeding. Treatment with COX-2 inhibitors is associated with a high incidence of exacerbation of the underlying IBD and GI-related complications.

Adult↗
PubMed2004

Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.

BACKGROUND: 6-Thioguanine (6-TG) has been used as an alternative thiopurine for inflammatory bowel disease (IBD) patients not responsive to or intolerant of azathioprine (AZA) and 6-mercaptopurine (6-MP). 6-TG-related hepatotoxicity, including liver biochemistry value elevations, sinusoidal collagen deposition on electron microscopy, and veno-occlusive disease, have been described related to its use as therapy for neoplastic disease. METHODS: We studied 38 liver biopsies from patients treated with 6-TG, almost all of whom (n = 125) received 6-TG for 1 to 3 years at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center. All biopsies were fixed in 4% buffered formalin and prepared in the usual manner. Hematoxylin and eosin, Masson's trichrome (trichrome), and reticulin silver impregnation (reticulin) stained slides were studied. In 23 cases, tissue was also prospectively fixed in glutaraldehyde and processed for electron microscopy. RESULTS: In 20 of the 37 patients studied (53%), nodular regeneration of varying degree was seen with reticulin. In only 4 of these 20 instances (11% of the total) were the changes seen with hematoxylin and eosin and in 3 of the 4, only in retrospect after studying the reticulin preparation. Minimal fibrosis was seen with trichrome in only 13 biopsies (34%), but sinusoidal collagen deposition was observed in 14 of the 23 cases studied with electron microscopy (60%). The biopsy from the 1 patient with nodular hyperplasia obvious with hematoxylin and eosin also demonstrated changes of venous outflow obstruction. CONCLUSIONS: 6-TG-treated IBD patients are at significant risk for nodular hyperplasia, early fibrosis and, less often, venous outflow disease (Budd-Chiari). The natural history of these changes is unknown and follow-up biopsies are needed to determine histologic and clinical sequela. Patients not demonstrating nodular hyperplasia or fibrosis who continue with 6-TG because there are no better therapeutic choices should be periodically rebiopsied.

Adolescent↗
PubMed2003

Human intestinal epithelial cells are broadly unresponsive to Toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut.

Intestinal epithelial cells (IEC) interact with a high density of Gram-positive bacteria and are active participants in mucosal immune responses. Recognition of Gram-positive organisms by Toll-like receptor (TLR)2 induces proinflammatory gene expression by diverse cells. We hypothesized that IEC are unresponsive to Gram-positive pathogen-associated molecular patterns and sought to characterize the functional responses of IEC to TLR2-specific ligands. Human colonic epithelial cells isolated by laser capture microscopy and IEC lines (Caco-2, T84, HT-29) were analyzed for expression of TLR2, TLR6, TLR1, and Toll inhibitory protein (Tollip) mRNA by RT-PCR and quantitative real-time PCR. Response to Gram-positive bacterial ligands was measured by NF-kappa B reporter gene activation and IL-8 secretion. TLR2 protein expression was analyzed by immunofluorescence and flow cytometry. Colonic epithelial cells and lamina propria cells from both uninflamed and inflamed tissue demonstrate low expression of TLR2 mRNA compared with THP-1 monocytes. IECs were unresponsive to TLR2 ligands including the staphylococcal-derived Ags phenol soluble modulin, peptidoglycan, and lipotechoic acid and the mycobacterial-derived Ag soluble tuberculosis factor. Transgenic expression of TLR2 and TLR6 restored responsiveness to phenol soluble modulin and peptidoglycan in IEC. In addition to low levels of TLR2 protein expression, IEC also express high levels of the inhibitory molecule Tollip. We conclude that IEC are broadly unresponsive to TLR2 ligands secondary to deficient expression of TLR2 and TLR6. The relative absence of TLR2 protein expression by IEC and high level of Tollip expression may be important in preventing chronic proinflammatory cytokine secretion in response to commensal Gram-positive bacteria in the gut.

Bacterial Toxins↗
PubMed2003

6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.

BACKGROUND & AIMS: Thioguanine (6-TG) has been studied as an alternative thiopurine in inflammatory bowel disease (IBD). Short-term safety and efficacy data were favorable. Experience with 6-TG in patients with acute lymphoblastic leukemia raised long-term safety concerns when implicated in nodular regenerative hyperplasia (NRH) of the liver and portal hypertension. The aim of this study was to describe the association between 6-TG and NRH in IBD. METHODS: Liver chemistries and complete blood counts were monitored, and patients were encouraged to undergo liver biopsy. Clinical data were collected by chart review, and associations were tested by univariate and multivariable analyses. Patients were classified based on the presence (group 1) or absence (group 2) of laboratory abnormalities. RESULTS: Laboratory abnormalities occurred in 29 of 111 patients (26%). Elevations of liver enzymes and a decrease in platelet counts (<200,000) were most commonly observed. Male gender (odds ratio, 2.9; 95% CI, 1.1-7.3; P < 0.03) and preferential 6-methylmercaptopurine production on 6-mercaptopurine/azathioprine (odds ratio, 3.0; 95% CI, 1.2-7.4; P < 0.04) were independently associated with laboratory abnormalities. No association was seen with duration of 6-TG treatment, cumulative dose, or 6-TG nucleotide levels. The median increase in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels was 39, 30, and 75 U/L, respectively, in group 1, and the median decrease in platelet count was 115,000 in group 1 versus 7000 in group 2 (P < 0.001). NRH occurred in 76% of patients undergoing biopsy in group 1 and 33% in group 2. CONCLUSIONS: NRH is a common finding in 6-TG-treated patients with IBD. The progression or reversibility of NRH remains unknown. Our findings suggest that 6-TG should not be considered as therapy for patients with IBD.

Adolescent↗
PubMed2003

Immunologic regulation of toll-like receptors in gut epithelium.

PURPOSE OF REVIEW: In response to the presence of pathogens in the environment, the innate immune system has evolved to provide a rapid defense against microbes. This response involves the recognition of molecular patterns present in diverse microbes by a series of receptors termed toll-like receptors. The focus of this article is the regulation of toll-like receptor signaling in the intestinal epithelium. The intestinal epithelium is continually exposed to a high concentration of diverse bacteria. In spite of the density of commensal bacteria, the normal intestine is not inflamed. Idiopathic inflammatory bowel disease in humans and animals is characterized by aberrant host-microbial interactions. RECENT FINDINGS: Several studies demonstrate that intestinal epithelial cells are poorly responsive to microbial products. The reason for this hyporesponsiveness is decreased or polarized expression of toll-like receptor molecules. Inflammatory cytokines upregulate expression of toll-like receptors. SUMMARY: The intestinal epithelium has evolved under the pressure of the microbiota to mute a response to commensal bacteria while maintaining the ability to respond to pathogens. In inflammatory bowel disease, the loss of tolerance to the normal flora may be due in part to inappropriate toll-like receptor signaling.

Journal Article↗
PubMed2003

Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine.

OBJECTIVE: Approximately 10% of inflammatory bowel disease (IBD) patients receiving 6-mercaptopurine (6-MP) or azathioprine (AZA) develop drug hypersensitivity reactions necessitating early discontinuation of these traditional thiopurines. These allergic reactions typically reoccur upon rechallenge. Our recently published pilot study suggested that thioguanine (6-TG), a closely related thiopurine, was efficacious and well tolerated in IBD patients resistant to 6-MP/AZA. The aim of this study was to determine if hypersensitivity reactions to 6-MP/AZA reoccur with 6-TG therapy. METHODS: IBD patients allergic to 6-MP and/or AZA were treated with 6-TG as an alternate thiopurine. Hypersensitivity reactions to 6-MP/AZA must have been documented within 6 wk of 6-MP/AZA initiation. RESULTS: 6-TG was initiated in 21 IBD patients at a median (range) dose of 20 (10-40) mg/day. 6-TG hypersensitivity reaction occurred in only four of 21 (19%) patients after a median time interval of 9 days. Pancreatitis did not reoccur with 6-TG. Eighty-two percent of 6-TG tolerant patients were assessed as improved at last follow-up. CONCLUSIONS: These results suggest that 6-TG may be considered as a possible alternate thiopurine in patients allergic to traditional 6-MP/AZA. Despite these favorable results, candidates for 6-TG should be selected with caution, and its use should be reserved for IBD patients well informed about potential toxicities.

Adult↗
PubMed2003

TLR signaling at the intestinal epithelial interface.

The intestinal epithelium provides a critical interface between lumenal bacteria and the mucosal immune system. Whereas normal commensal flora do not trigger acute inflammation, pathogenic bacteria trigger a potent inflammatory response. Our studies emanate from the hypothesis that the intestinal epithelium is normally hyporesponsive to commensal pathogen-associated molecular patterns (PAMPs) such as LPS. Our data demonstrate that normal human colonic epithelial cells and lamina propria cells express low levels of TLR4 and its co-receptor MD-2. This expression pattern is mirrored by intestinal epithelial cell (IEC) lines. Co-expression of TLR4 and MD-2 is necessary and sufficient for LPS responsiveness in IEC. Moreover, LPS sensing occurs along the basolateral membrane of polarized IEC in culture. Expression of MD-2 is regulated by IFN-gamma. Cloning of the MD-2 promoter demonstrates that promoter activity is increased by IFN-gamma and blocked by the STAT inhibitor SOCS3. We conclude from our studies that the intestinal epithelium down-regulates expression of TLR4 and MD-2 and is LPS unresponsive. The Th1 cytokine IFN-gamma up-regulates expression of MD-2 in a STAT-dependent fashion. The results of our studies have important implications for understanding human inflammatory bowel diseases.

Antigens, Surface↗
PubMed2002

TLR4 and MD-2 expression is regulated by immune-mediated signals in human intestinal epithelial cells.

The normal intestinal epithelium is not inflamed despite contact with a high density of commensal bacteria. Intestinal epithelial cells (IEC) express low levels of TLR4 and MD-2 and are lipopolysaccharide (LPS)-unresponsive. We hypothesized that immune-mediated signals regulate the expression of TLR4 and MD-2 in IEC. Expression of TLR4 and MD-2 was examined in normal colonic epithelial cells or intestinal epithelial cell lines. The effect of the cytokines interferon (IFN)-gamma, IFN-alpha, and tumor necrosis factor-alpha (TNF-alpha) on TLR4 and MD-2 expression was examined by reverse transcription-PCR and Western blot. NF-kappaB transcriptional activation and interleukin-8 secretion were used as measures of LPS responsiveness. Native colonic epithelial cells and IEC lines express a low level of TLR4 and MD-2 mRNA. IFN-gamma regulates MD-2 expression in both IEC lines, whereas IFN-gamma and TNF-alpha regulate TLR4 mRNA expression in IEC lines. Pre-incubation with IFN-gamma and/or TNF-alpha sensitizes IEC to LPS-dependent interleukin-8 secretion. To examine MD-2 transcriptional regulation, we cloned a 1-kb sequence proximal to the MD-2 gene translational start site. This promoter directed expression of a reporter gene in endothelial cells and IEC. IFN-gamma positively regulated MD-2 promoter activity in IEC. Co-expression of a STAT inhibitor, SOCS3, blocked IFN-gamma-mediated MD-2 promoter activation. T cell-derived cytokines lead to increased expression of TLR4 and MD-2 and LPS-dependent pro-inflammatory cytokine secretion in IEC. IFN-gamma regulates expression of the critical TLR4 co-receptor MD-2 through the Janus tyrosine kinase-STAT pathway. Th1 cytokines may initiate or perpetuate intestinal inflammation by altering toll-like receptor expression and bacterial reactivity.

Antigens, Surface↗
PubMed2002

The pathogenesis of inflammatory bowel disease: translational implications for clinicians.

Research in the pathogenesis of inflammatory bowel disease (IBD) has dramatically broadened our understanding of these complex disorders. These clinical manifestations result from a dysregulated immune response in the presence of luminal bacteria. Recent identification of mutations in the NOD2 gene, a protein involved in the sensing of bacteria, offers genetic support for the model of perturbed host-microbial interactions in Crohn's disease. Several immunologic pathways have been identified that play a role in maintaining gut immune homeostasis. Abnormal expression of proinflammatory, deleterious cytokines such as tumor necrosis factor-a and interferon-g results in direct and indirect tissue damage. The search for specific causative microbial agents in IBD continues to be intense. This paper describes the advances in our understanding of IBD pathogenesis, with an emphasis on how this information is translated into patient care. The next stage of research will take advantage of such molecular biologic techniques to identify new pathogenetic mechanisms and targets for therapy tailored to individual patients.

Animals↗
PubMed2002

6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.

BACKGROUND & AIMS: Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT. METHODS: Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information. RESULTS: Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation. CONCLUSIONS: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.

Adolescent↗
PubMed2002

Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease.

BACKGROUND & AIMS: The clinical manifestations of Crohn's disease (CD) are diverse, ranging from fibrostenosing small-bowel disease to colon-predominant inflammation. These distinctions may represent genetic, immunologic, and microbial heterogeneity. NOD2 gene mutations in CD have been described recently and may alter innate immune responses. We hypothesized that NOD2 mutations may be associated with distinct phenotypic expressions of CD. METHODS: Two cohorts of consecutively identified patients referred to an inflammatory bowel disease center (n = 142 collected between 1993 and 1996; n = 59 collected between 1999 and 2001) were genotyped for 3 single nucleotide variants of NOD2-R675W, G881R, and 3020insC-and phenotyped for disease behavior, disease location, and serum immune markers. RESULTS: Univariate analysis showed that CD-associated NOD2 variants were significantly associated with fibrostenosing disease in each cohort (P = 0.049 and P = 0.002, respectively). When both cohorts were analyzed together, the association between NOD2 variants and fibrostenosing disease was more significant (P = 0.001). These relationships were observed in both Jews and non-Jews. Forty-six percent of patients with fibrostenosing disease carried at least 1 of these alleles, compared with only 23.5% of patients without fibrostenosing disease (odds ratio, 2.8; 95% confidence interval, 1.6-5.2). Multivariate and conditioning analyses showed a primary association between NOD2 allelic variants and fibrostenosing disease, but not with small-bowel disease. CONCLUSIONS: In this description of a genotype/phenotype correlation in CD patients and NOD2 variants, data suggest that variation in this gene contributes to the occurrence of fibrostenotic CD of the small bowel.

Adolescent↗