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Biomedical subjects

Robin G Lorenz

Publications and source records attributed to Robin G Lorenz.

14 recordsLinked to original sources
PubMed2006

Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study.

BACKGROUND & AIMS: The safety of selective cyclooxygenase-2 inhibitors in patients with ulcerative colitis in remission is unknown. METHODS: We performed a placebo-controlled pilot trial to evaluate the safety of celecoxib in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy. A total of 222 patients with ulcerative colitis in remission were randomized to receive oral celecoxib 200 mg or placebo twice daily for 14 days. Remission was defined as a total Mayo Clinic score of 2 points or less and an endoscopic score of 1 point or less. Disease exacerbation was defined as a total Mayo Clinic score of 5 points or more and an increase in the endoscopic score of 1 point or more. The primary analysis was disease exacerbation through day 14 among patients who underwent randomization, had at least 1 dose of study drug, and had both endoscopy and Mayo Clinic disease activity index scores at the baseline and final assessments. RESULTS: Three percent of patients in the celecoxib group experienced disease exacerbation through day 14, as compared with 4% in the placebo group (P = .719). Eleven percent of patients in each group experienced a bowel-related adverse event (P > .20). CONCLUSIONS: Therapy with celecoxib for up to 14 days did not have a greater relapse rate than placebo in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy.

Adolescent↗
PubMed2005

Animal models of intestinal inflammation: ineffective communication between coalition members.

The microbiota, epithelial cells, and mucosal immune cells in the intestine comprise an important gastrointestinal coalition. The intestinal microbiota can exert both beneficial as well as deleterious effects on their animal hosts. They interact with the innate defenses provided by epithelial cells through microbial recognition receptors. This communication, under normal conditions, results in a state of controlled inflammation. This article will focus on several animal models of intestinal inflammation, in which spontaneous or induced mutations or other genetic manipulations result in severe alterations in one of the members of the gastrointestinal coalition. These animal models of colitis have shown that alterations in communication between members of this coalition ultimately lead to gastrointestinal disease.

Animals↗
PubMed2005

Organizing a mucosal defense.

Gastrointestinal associated lymphoid tissue can be divided into loosely organized effector sites, which include the lamina propria and intraepithelial lymphocytes, and more organized structures, such as mesenteric lymph nodes (LNs), Peyer's patches (PPs), isolated lymphoid follicles, and cryptopatches (CPs). These organized structures in the gastrointestinal tract have been hypothesized to play the role of primary lymphoid organ, supporting the extrathymic development of T lymphocytes (CPs), secondary lymphoid organs involved in the induction of the mucosal immune response (PPs), and tertiary lymphoid structures whose function is still under debate (isolated lymphoid follicles). The most widely studied lymphoid structure found in the small intestine is the PP. PPs are secondary lymphoid structures, and their development and function have been extensively investigated. However, single lymphoid aggregates resembling PPs have been also described in humans and in the murine small intestines. These isolated lymphoid follicles have both germinal centers and an overlying follicle-associated epithelium, suggesting that they also can function as inductive sites for the mucosal immune response. This review compares and contrasts the development and function of the four main organized gastrointestinal lymphoid tissues: CPs, isolated lymphoid follicles, PPs, and mesenteric LNs.

Animals↗
PubMed2005

Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota.

There are now many experimental models of inflammatory bowel disease (IBD), most of which are due to induced mutations in mice that result in an impaired homeostasis with the intestinal microbiota. These models can be clustered into several broad categories that, in turn, define the crucial cellular and molecular mechanisms of host microbial interactions in the intestine. The first of these components is innate immunity defined broadly to include both myeloid and epithelial cell mechanisms. A second component is the effector response of the adaptive immune system, which, in most instances, comprises the CD4+ T cell and its relevant cytokines. The third component is regulation, which can involve multiple cell types, but again particularly involves CD4+ T cells. Severe impairment of a single component can result in disease, but many models demonstrate milder defects in more than one component. The same is true for both spontaneous models of IBD, C3H/HeJBir and SAMPI/Yit mice. The thesis is advanced that 'multiple hits' or defects in these interacting components is required for IBD to occur in both mouse and human.

Animals↗
PubMed2005

The Helicobacter felis model of adoptive transfer gastritis.

The bacterium Helicobacter pylori is a major human pathogen and the principal cause of acute and chronic gastritis, gastric and duodenal ulcer disease, and gastric adenocarcinoma. Infection with gastric Helicobacter results in an early infiltration of neutrophils, monocytes, and natural killer cells, followed by an influx of T cells and plasma cells. Although the critical components of this gastric infiltrate that lead to disease are unclear, the Helicobacter felis-infected mouse and other mouse models of Helicobacter-associated gastritis have demonstrated the critical nature of adaptive immunity in the development of gastric epithelial pathology. To further investigate the role of adaptive immunity in this disease, adoptive transfer models of disease have also been utilized. These models clearly demonstrate that it is the host CD4+ T lymphocyte response that is crucial for the development of Helicobacter-associated gastric epithelial changes.

Adoptive Transfer↗
PubMed2004

Isolated lymphoid follicles can function as sites for induction of mucosal immune responses.

Isolated lymphoid follicles (ILFs) are organized lymphoid structures in the small intestine. ILFs were recently identified in the murine small intestine; however, the function of ILFs is unknown. To better understand ILFs and the role they play in the intestinal immune response, we have examined the composition of ILFs, the factors that are involved in the genesis of ILFs, and the ability of ILFs to support antigen-specific immunoglobulin production. We found that ILFs contain predominantly B-2 B lymphocytes, and CD4(+) TCRbeta(+) T lymphocytes. Similar to the formation of Peyer's patches (PPs), lymphotoxin beta receptor (LTbetaR)-dependent events are required for ILF formation; however, the timing of these events and the cellular source of LT differ. ILF formation can occur de novo in response to luminal stimuli and requires LT-sufficient B lymphocytes and TNF receptor I function for full maturation. The epithelium over ILFs resembles the PP follicle-associated epithelium, as M cells are present and pathogens such as Yersinia can be bound and taken up into the underlying follicle. Total fecal IgA production is not augmented in animals possessing ILFs; however, the production of antigen-specific IgA is increased in animals possessing ILFs orally challenged with Salmonella typhimurium. Similar to PPs, ILFs can support antigen-specific IgA production following oral immunization. These findings support the concept that ILFs are formed in response to mucosal challenges, and may play a physiological role in the production of antigen-specific intestinal IgA.

Animals↗
PubMed2003

TNFR1 mediates the radioprotective effects of lipopolysaccharide in the mouse intestine.

LPS is radioprotective in the mouse small intestine through a mechanism that includes the synthesis of cyclooxygenase-2 (COX-2) and PGE2. The goal of this study was to identify the intermediate steps in this process. We used wild-type (WT) C57BL/6 mice and knockouts for tumor necrosis factor receptors 1 and 2 (TNFR1-/-, TNFR2-/-) and recombination-activating gene 1-/- mice. Mice were given parenteral LPS and then subjected to 12 Gy total body gamma irradiation. The number of surviving intestinal crypts was assessed 3.5 days after irradiation using a clonogenic assay. Crypt cell apoptosis was assessed by histology. Parenteral administration of LPS induced COX-2 expression, PGE2 production, and radioprotection in WT and TNFR2-/- mice but not in TNFR1-/- mice. TNFR1-/- mice were radioprotected by administration of exogenous 16,16-dimethyl PGE2. Immunohistochemical studies localized TNFR1 and COX-2 expression to subeptihelial fibroblasts and villus epithelial cells. Radiation-induced apoptosis was reduced by pretreatment with LPS in WT and TNFR2-/- mice but not in TNFR1-/- mice. In the absence of LPS, crypt survival was elevated in TNFR1-/- when compared with WT mice. These findings demonstrate that TNFR1 function is required for LPS-induced radioprotection in C57BL/6 mice and define an essential role for TNFR1 function in the induction of COX-2 expression and PGE2 production in this process. The immunolocalization of TNFR1 and COX-2 expression to subepithelial fibroblasts following LPS administration suggests that this cell type plays an intermediate role in LPS-induced radioprotection in the intestine.

16,16-Dimethylprostaglandin E2↗
PubMed2003

Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, and TNF receptor I function.

The gastrointestinal mucosa contains a complex network of lymphoid compartments that have evolved to efficiently protect the host from invading pathogens. Recently, an additional lymphoid structure resembling Peyer's patches (PP) in composition and architecture has been identified in the murine small intestine, the isolated lymphoid follicle (ILF). In this study we examine the nature and factors required for ILF formation. We observed a spectrum of structures fitting the previous descriptions of ILFs, ranging from clusters of B220(+) cells (which we have termed immature ILFs) to well-organized lymphoid nodules (which we have termed mature ILFs). Here we demonstrate that that similar to PP formation, ILF formation requires lymphotoxin (LT)- and LT beta receptor-dependent events. However unlike PP formation, the LT- and LT beta receptor-dependent events required for ILF formation can occur in adulthood and require LT-sufficient B lymphocytes. We demonstrate that mature ILF formation occurs in response to lumenal stimuli, including normal bacterial flora, and requires TNF receptor I function. These findings suggest that ILFs are organized intestinal lymphoid structures whose formation can be induced and whose mass can be expanded in response to mucosal challenges.

Aging↗
PubMed2003

Toll-like receptor 4 on stromal and hematopoietic cells mediates innate resistance to uropathogenic Escherichia coli.

Innate host defenses at mucosal surfaces are critical in the early stages of many bacterial infections. In addition to cells of the traditional innate immune system, epithelial cells can also produce inflammatory mediators during an infection. However, the role of the epithelium in innate host defense in vivo is unclear. Recent studies have shown that lipopolysaccharide (LPS) recognition is critical for bladder epithelial cells to recognize and respond to Escherichia coli. Moreover, the LPS-nonresponsive mouse strain C3HHeJ, which has a mutation in the primary LPS receptor, Toll-like receptor 4 (TLR4), is extremely susceptible to infection with uropathogenic strains of E. coli. In this study, a bone marrow transplant approach was used to investigate the specific contributions of the bladder epithelium (and other stromal cells) in the TLR4-mediated innate immune response to the invading E. coli pathogen. Mice expressing the mutant TLR4 in the epithelialstromal compartment were not able to mount a protective inflammatory response to control the early infection even when their hematopoietic cells expressed wild-type TLR4. However, the presence of TLR4(+) epithelialstromal cells was not sufficient to activate an acute inflammatory response unless the hematopoietic cells were also TLR4(+). These results demonstrated that bladder epithelial cells play a critical role in TLR4-mediated innate immunity in vivo during a mucosal bacterial infection.

Animals↗
PubMed2003

CD14- and Toll-like receptor-dependent activation of bladder epithelial cells by lipopolysaccharide and type 1 piliated Escherichia coli.

The gram-negative bacterium Escherichia coli is the leading cause of urinary tract infection. The interaction between type 1 piliated E. coli and bladder epithelial cells leads to the rapid production of inflammatory mediators, such as interleukin-6 (IL-6) and IL-8. Conflicting reports have been published in the literature regarding the mechanism by which uroepithelial cells are activated by type 1 piliated E. coli. In particular, the role of lipopolysaccharide (LPS) in these responses has been an area of significant debate. Much of the data arguing against LPS-mediated activation of bladder epithelial cells have come from studies using a renal epithelial cell line as an in vitro model of the urinary epithelium. In this report, we analyzed three bladder epithelial cell lines and demonstrated that they all respond to LPS. Furthermore, the LPS responsivity of the cell lines directly correlated with their ability to generate IL-6 after E. coli stimulation. The LPS receptor complex utilized by the bladder epithelial cell lines included CD14 and Toll-like receptors, and signaling involved the activation of NF-kappaB and p38 mitogen-activated protein kinase. Also, reverse transcription-PCR analysis demonstrated that bladder epithelial cells express CD14 mRNA. Thus, the molecular machinery utilized by bladder epithelial cells for the recognition of E. coli is very similar to that described for traditional innate immune cells, such as macrophages. In contrast, the A498 renal epithelial cell line did not express CD14, was hyporesponsive to LPS stimulation, and demonstrated poor IL-6 responses to E. coli.

Drosophila Proteins↗
PubMed2002

A gnotobiotic transgenic mouse model for studying interactions between small intestinal enterocytes and intraepithelial lymphocytes.

The mouse intestinal epithelium undergoes continuous renewal throughout life. Intraepithelial lymphocytes (IELs) represent a significant fraction of this epithelium and play an important role in intestinal mucosal barrier function. We have generated a germ-free transgenic mouse model to examine the effects of a genetically engineered proliferative abnormality in the principal epithelial cell lineage (enterocytes) on IEL census and on IEL-enterocytic cross-talk. SV40 large T antigen (TAg(Wt)) or a mutant derivative (TAg(K107/8)) that does not bind pRB was expressed in small intestinal villus enterocytes under the control of elements from the intestinal fatty acid binding protein gene (Fabpi). Quantitative immunohistochemical and flow cytometric analyses of conventionally raised and germ-free FVB/N Fabpi-TAg(Wt), Fabpi-TAg(K107/8), and nontransgenic mice disclosed that forced reentry of enterocytes into the cell cycle is accompanied by an influx of thymically educated alphabeta T cell receptor (TCR)(+) CD4(+) and alphabeta TCR(+) CD8alphabeta(+) IELs and a decrease in intestinally derived gammadelta TCR(+) CD8alphaalpha IELs. Real time quantitative reverse transcriptase-PCR studies of jejunal villus epithelium recovered from germ-free transgenic and normal mice by laser capture microdissection and gammadelta TCR(+) jejunal IELs purified by flow cytometry disclosed that the proliferative abnormality is accompanied by decreased expression of enterocytic interleukin-7 as well as IEL interleukin-7Ralpha and transforming growth factor beta3. The analysis also revealed that normal villus epithelium expresses Fms-like tyrosine kinase 3 (Flt3), a known regulator of hematopoietic stem cell proliferation and neuronal cell survival, and its ligand (Flt3L). Epithelial expression of this receptor and its ligand is reduced by the proliferative abnormality, whereas IEL expression of Flt3L remains constant. Together, these findings demonstrate that changes in the proliferative status of the intestinal epithelium affects maturation of gammadelta TCR(+) IELs and produces an influx of alphabeta TCR(+) IELs even in the absence of a microflora.

Animals↗
PubMed2002

Postgestational lymphotoxin/lymphotoxin beta receptor interactions are essential for the presence of intestinal B lymphocytes.

Lymphotoxin (LT), a cytokine belonging to the TNF family, has established roles in the formation of secondary lymphoid structures and in the compartmentalization of T and B lymphocyte areas of the spleen. In this study, we examine the role of LT in directing the composition of intestinal lymphocytes. We report that mice deficient in LT have a normal composition of intestinal lamina propria (LP) T lymphocytes, and an absence of intestinal LP B lymphocytes. We further refine this observation to demonstrate that the interaction of LT with the LTbetaR is essential for the presence LP B lymphocytes. The LT/LTbetaR-dependent events relevant for the presence of LP B lymphocytes occur after birth, do not require the presence of Peyer's patches, lymph nodes, or the spleen; and therefore, are distinct and independent from the previously identified roles of LT/LTbetaR. The LT-dependent signal relevant for the presence of LP B lymphocytes is optimally supplied by a LT-sufficient B lymphocyte, and requires a LTbetaR-sufficient radio-resistant, non-bone marrow-derived cell. Based upon the severity of the deficit of LP B lymphocytes we observed, these novel LT/LTbetaR-dependent events are of primary importance in directing the entry and residence of LP B lymphocytes.

Animals↗
PubMed2002

Effect of trimethoprim-sulfamethoxazole on recurrent bacteriuria and bacterial persistence in mice infected with uropathogenic Escherichia coli.

One of the more perplexing aspects of urinary tract infections (UTIs) is their high propensity to recur. It has been proposed that recurrent infections are a result of the reintroduction of bacteria from the gastrointestinal tract (GIT) to the urinary tract (UT); however, since a significant subset of recurrent UTIs are caused by an identical bacterial strain, it has been challenging to formally prove this hypothesis for same-strain recurrences by using epidemiologic approaches. We present data here obtained by using a mouse model of UTIs in which it was shown that 36% (5 of 14) of mice infected with uropathogenic Escherichia coli (UPEC) will have at least one bacteriuric recurrence, with 21% (3 of 14) having more than one recurrence during a 6-week period after an acute UTI. Intraurethrally infected mice develop UPEC reservoirs in both their feces and their bladders. Ten days of trimethoprim-sulfamethoxazole (SXT) therapy reduces urinary recurrences and eradicates fecal colonization, whereas 3 days of SXT treatment has no effect over a twenty-eight-day observation period despite clearing fecal colonization acutely. Interestingly, SXT is unable to eradicate bacteria from the bladder reservoir even after a 10-day treatment regimen, thus demonstrating that the bladder reservoir can persist even in the face of long-term antibiotic therapy.

Animals↗