Matthew B. Grisham

Texas Tech University Health Sciences Center, El Paso, Texas, United States

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Publications (367)2025.57 Total impact


  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases and assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient's bedside, it is becoming increasingly apparent that the mouse immune system is substantially different from the human. Indeed, it is well known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation, and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system to address important human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hematolymphoid cells in mice would provide investigators with a relatively inexpensive small animal model to study clinically relevant mechanisms and facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss the use of these unique mouse models to define the human-specific immunopathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.
    Full-text · Article · May 2015 · Inflammatory Bowel Diseases
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    Kai Fang · Matthew B. Grisham · Christopher G. Kevil
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    ABSTRACT: Experimental models of colitis in mice have been used extensively for analyzing the molecular events that occur during inflammatory bowel disease (IBD) development. However, it is uncertain to what extent the experimental models reproduce features of human IBD.This is largely due to the lack of precise methods for direct and comprehensive comparison of mouse and human inflamed colon tissue at the molecular level. Here, we use global gene expression patterns of two sets of pediatric IBD and two mouse models of colitis to obtain a direct comparison of the genome signatures of mouse and human IBD. By comparing the two sets of pediatric IBD microarray data, we found 83 genes were differentially expressed in a similar manner between pediatric Crohn’s disease and ulcerative colitis. Up-regulation of the chemokine (C–C motif) ligand 2 (CCL2) gene that maps to 17q12, a confirmed IBD susceptibility loci, indicates that our comparison study can reveal known genetic associations with IBD. In comparing pediatric IBD and experimental colitis microarray data, we found common signatures amongst them including: (1) up-regulation of CXCL9 and S100A8; (2) cytokine–cytokine receptor pathway dysregulation; and (3) over-represented IRF1 and IRF2 transcription binding sites in the promoter region of up-regulated genes, and HNF1A and Lhx3 binding sites were over-represented in the promoter region of the downregulated genes. In summary, this study provides a comprehensive view of transcriptome changes between different pediatric IBD populations in comparison with different colitis models. These findings reveal several new molecular targets for further study in the regulation of colitis.
    Full-text · Article · Apr 2015 · Frontiers in Immunology
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    Kai Fang · Matthew B. Grisham · Christopher G. Kevil
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    ABSTRACT: Experimental models of colitis in mice have been used extensively for analyzing the molecular events that occur during inflammatory bowel disease (IBD) development. However, it is uncertain to what extent the experimental models reproduce features of human IBD.This is largely due to the lack of precise methods for direct and comprehensive comparison of mouse and human inflamed colon tissue at the molecular level. Here, we use global gene expression patterns of two sets of pediatric IBD and two mouse models of colitis to obtain a direct comparison of the genome signatures of mouse and human IBD. By comparing the two sets of pediatric IBD microarray data, we found 83 genes were differentially expressed in a similar manner between pediatric Crohn’s disease and ulcerative colitis. Up-regulation of the chemokine (C–C motif) ligand 2 (CCL2) gene that maps to 17q12, a confirmed IBD susceptibility loci, indicates that our comparison study can reveal known genetic associations with IBD. In comparing pediatric IBD and experimental colitis microarray data, we found common signatures amongst them including: (1) up-regulation of CXCL9 and S100A8; (2) cytokine–cytokine receptor pathway dysregulation; and (3) over-represented IRF1 and IRF2 transcription binding sites in the promoter region of up-regulated genes, and HNF1A and Lhx3 binding sites were over-represented in the promoter region of the downregulated genes. In summary, this study provides a comprehensive view of transcriptome changes between different pediatric IBD populations in comparison with different colitis models. These findings reveal several new molecular targets for further study in the regulation of colitis.
    Full-text · Article · Apr 2015 · Frontiers in Immunology
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    ABSTRACT: It is well-known that intestinal microbiota are required for the induction of chronic gut inflammation in the CD4CD45RB→ RAG-1 mouse model of chronic colitis. Following our relocation from LSU Health Sciences Center (LSUSHC) to Texas Tech University Health Sciences Center (TTUHSC), we observed a significant reduction in the incidence and severity of disease (30-40%) compared to our previous 15 year history of ∼85% at LSUHSC. The objectives of this study were to: a) ascertain whether differences in the gut microbiota may account for the differences in disease incidence and b) determine whether colonization of RAG-1 (RAG ko) mice with feces obtained from colitic mice increases the incidence and severity of colitis in the T cell transfer model. DNA from freshly frozen feces was isolated using standard protocols and 16S rRNA sequencing was performed using the Roche 454 platform. For some studies, mice were colonized (via gastric gavage) with 40 mg donor feces 1 week prior to adoptive transfer of naïve (CD4CD45RB) T-cells. Microbiome analysis revealed marked shifts in the relative abundance of several major bacterial communities present in feces obtained from LSUHSC versus TTUHSC mice. For example, the relative abundance of Firmicutes and Bacteroidetes was ∼70 and 20%, respectively in healthy TTUHSC-RAG ko mice whereas these same 2 phyla represented 48 and 50%, respectively in healthy LSUHSC-RAG ko animals. Interestingly, the fecal microbiota from TTUHSC-RAG ko mice revealed significantly higher abundances of Proteobacteria, Verrucomicrobia and Tenericutes when compared to the microbiota obtained from healthy LSUHSC-RAG ko mice. Not surprisingly, induction of chronic colitis in LSUHSC-RAG ko mice via adoptive transfer of naïve T cells, produced a marked dysbiosis most notably characterized by an increased abundance of Verrucomicrobia together with corresponding and marked decrease in Bacteroidetes. Adoptive transfer of naive T cells into healthy TTUHSC-RAG ko mice that were first colonized with healthy LSUHSC-RAG ko feces induced mild-to-moderate colitis in ∼80% of the mice at 8 weeks post T cell transfer. In addition, we found that T cell transfer into TTUHSC-RAG ko mice that were first colonized with feces from colitic LSUHSC-RAG ko mice induced robust colitis in >90% of these recipients (called LSUHSCc→TTUHSC mice). Furthermore, T cell transfer into TTUHSC-RAG ko mice that had been colonized with feces from colitic LSUHCc→TTUHSC mice induced moderate-to-severe colitis in virtually all (>98%) of these recipients (called TTUHSCc→TTUHSC mice). Importantly, colonization of healthy wild type mice or TTUHSC-RAG ko mice (in the absence of T cell transfer) with colitic feces from TTUHSCc→TTUHSC mice did not induce disease over the 8 week observation period. We conclude that colonization of healthy RAG ko mice with dysbiotic microbiota obtained from colitic mice markedly increases the severity and incidence of chronic colitis in the T cell transfer model. Our data also suggest that the increase in severity and incidence of disease is not due to the presence of intestinal pathogens and can only be produced in mice with a dysregulated immune system (supported by grants from the DOD-W81XWH-11-1-0666 and NIH- RO1 DK 091269).
    No preview · Article · Dec 2014 · Inflammatory Bowel Diseases
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    Yava L Jones-Hall · Matthew B Grisham
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    ABSTRACT: Inflammatory bowel diseases (IBD) are chronic, relapsing conditions of multifactorial etiology. The two primary diseases of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both entities are hypothesized to occur in genetically susceptible individuals due to microbial alterations and environmental contributions. The exact etiopathogenesis, however, is not known for either disease. A variety of mouse models of CD and UC have been developed to investigate the pathogenesis of these diseases and evaluate treatment modalities. Broadly speaking, the mouse models can be divided into 4 categories: genetically engineered, immune manipulated, spontaneous and erosive/chemically induced. No one mouse model completely recapitulates the immunopathology of CD or UC, however each model possesses particular similarities to human IBD and offers advantageous for specific details of IBD pathogenesis. Here we discuss the more commonly used models in each category and critically evaluate how the immunopathology induced compares to CD or UC, as well as the advantages and disadvantages associated with each model.
    Full-text · Article · May 2014 · Pathophysiology
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    E Kurmaeva · J D Lord · S Zhang · J R Bao · C G Kevil · M B Grisham · D V Ostanin
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    ABSTRACT: Anti-adhesion therapies that target α4 integrins (e.g., natalizumab) are thought to work by blocking T-cell recruitment to the intestinal tissues in patients with Crohn's disease (CD); however, little direct evidence is available to confirm this contention. We wished to evaluate the importance of T cell-associated α4 integrins in a chronic colitis model in mice and to determine the effect of natalizumab treatment on intestinal tissue T-cell accumulation in human CD. Adoptive transfer of T cells lacking α4 (α4(-/-)) but not β1 integrin into immunodeficient mice produced significantly attenuated disease. This was correlated with reduced numbers of colon CD4 T cells compared with the control mice; however, tissue distribution of T helper type 1 (Th1) and T helper type 17 (Th17) cells and regulatory T cells (Tregs) was not affected by the lack of α4. Furthermore, α4(-/-) T cells demonstrated defective homing to the chronically inflamed small intestines and colons. Finally, patients treated with natalizumab showed significant reduction in mucosal CD4 T cells and no skewing in the foxp3(+) Treg or T-bet(+)Th1 fractions thereof. These results demonstrate a direct role for T cell-associated α4β7 but not α4β1 integrins during initiation and perpetuation of chronic colitis. Moreover, our data demonstrated that natalizumab treatment reduced mucosal CD4 T-cell accumulation in CD patients.Mucosal Immunology advance online publication, 9 April 2014; doi:10.1038/mi.2014.22.
    Full-text · Article · Apr 2014 · Mucosal Immunology
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    ABSTRACT: Multiple sclerosis (MS) has been proposed to be an immune-mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune-mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune-mediated diseases, including MS. However, in virus-induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune-mediated pathology, Tregs may also suppress anti-viral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV-infected mice with ex vivo-generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin-10 production from B cells, CD4(+) T cells, and dendritic cells, which may contribute to the decreased CNS inflammation.
    Full-text · Article · Jan 2014 · Brain Pathology
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    Yava L. Jones-Hall · Matthew B. Grisham
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    ABSTRACT: Inflammatory bowel diseases (IBD) are chronic, relapsing conditions of multifactorial etiology. The two primary diseases of IBD are Crohn's disease (CD) and ulcerative colitis (UC). Both entities are hypothesized to occur in genetically susceptible individuals due to microbial alterations and environmental contributions. The exact etiopathogenesis, however, is not known for either disease. A variety of mouse models of CD and UC have been developed to investigate the pathogenesis of these diseases and evaluate treatment modalities. Broadly speaking, the mouse models can be divided into 4 categories: genetically engineered, immune manipulated, spontaneous and erosive/chemically induced. No one mouse model completely recapitulates the immunopathology of CD or UC, however each model possesses particular similarities to human IBD and offers advantageous for specific details of IBD pathogenesis. Here we discuss the more commonly used models in each category and critically evaluate how the immunopathology induced compares to CD or UC, as well as the advantages and disadvantages associated with each model.
    Full-text · Article · Jan 2014
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    ABSTRACT: The mammalian intestine encounters many more microorganisms than any other tissue in the body thus making it the largest and most complex component of the immune system. Indeed, there are greater than 100 trillion (10(14)) microbes within the healthy human intestine where the total number of genes derived from this diverse microbiome exceeds that of the entire human genome by at least 100-fold. Our coexistence with the gut microbiota represents a dynamic and mutually beneficial relationship that is thought to be a major determinant of health and disease. Because of the potential for intestinal microorganisms to induce local and/or systemic inflammation, the intestinal immune system has developed a number of immune mechanisms to protect the host from pathogenic infections while limiting the inflammatory tissue injury that accompanies these immune responses. Failure to properly regulate intestinal mucosal immunity is thought to be responsible for the inflammatory tissue injury observed in the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis). An accumulating body of experimental and clinical evidence strongly suggest that IBD results from a dysregulated immune response to components of the normal gut flora in genetically-susceptible individuals. The objective of this review is to present our current understanding of the role that enteric microbiota play in intestinal homeostasis and pathogenesis of chronic intestinal inflammation.
    Full-text · Article · Nov 2013 · Free Radical Biology and Medicine
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    ABSTRACT: Ocular disease is known widely to occur in a subset of patients experiencing inflammatory bowel diseases. Although this extraintestinal manifestation has been recognized for a number of years, the pathogenetic mechanisms responsible for this distant organ inflammatory response are unknown. In the current study, we used a T-cell transfer model of chronic colitis in mice in which we quantified colonic inflammation, ocular function (electroretinography), ocular blood flow (intravital microscopy of the retina), intraocular pressure, and retinal hypoxia. Ocular function in colitic mice was significantly impaired, with decreases in retinal b-wave amplitudes and oscillatory potentials. Moreover, retinal a waves and oscillatory potentials were delayed. Retinal blood flow was significantly reduced in the colitic mice, and this decrease in perfusion coupled with significant decreases in hematocrit would decrease oxygen delivery to the eye. Accordingly, mice with severe colitis showed increased levels of immunostaining for the hypoxia-dependent probe pimonidazole. Finally, intraocular pressures were found to be reduced in the colitic mice. Ocular disease occurs in a mouse model of chronic colitis, with retinal dysfunction seeming to be related to insufficient perfusion and oxygen delivery.
    No preview · Article · Jul 2013 · Inflammatory Bowel Diseases
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    ABSTRACT: : The objectives of this study were to (a) evaluate and compare the ability of ex vivo-generated induced regulatory T cells (iTregs) and freshly isolated natural Tregs (nTregs) to reverse/attenuate preexisting intestinal inflammation in a mouse model of chronic colitis and (b) quantify the Treg-targeted gene expression profiles of these two Treg populations. We found that ex vivo-generated iTregs were significantly more potent than nTregs at attenuating preexisting colitis. This superior therapeutic activity was associated with increased accumulation of iTregs within the mesenteric lymph nodes and large and significant reductions in interleukin (IL)-6 and IL-17A expression in the colons of iTreg- versus nTreg-treated mice. The enhanced immunosuppressive activity of iTregs was not because of increased expression or stability of Foxp3 as iTregs and nTregs obtained from the mesenteric lymph nodes, and colons of reconstituted mice expressed similar levels of this important transcription factor. In addition, we observed a total of 27 genes that were either upregulated or downregulated in iTregs when compared with nTregs. Although iTregs were found to be superior at reversing established disease, their message levels of IL-10 and IL-35 and surface expression of the gut-homing molecules CCR9 and α4β7 were significantly reduced when compared with nTregs. Taken together, our data demonstrate that ex vivo-generated iTregs are significantly more potent than nTregs at attenuating preexisting gut inflammation despite reduced expression of classical regulatory cytokines and gut-homing molecules. Our data suggest that the immunosuppressive activity of iTregs may be because of their ability to directly or indirectly decrease expression of IL-6 and IL-17A within the inflamed bowel.
    Full-text · Article · Jul 2013 · Inflammatory Bowel Diseases
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    ABSTRACT: Background: Approximately one-half of patients with inflammatory bowel disease (IBD) suffer from anemia, with the most prevalent cause being iron deficiency. Accompanying the anemia are increases in erythropoietin, a plasma protein that can initiate the feedback production of new red blood cells. Anemia also occurs in animal models that are used to investigate the mechanisms of IBD; however, the extent to which iron deficiency produces the anemia in these animal models is unknown. Also unknown in the different animal models of IBD is whether the anemia upregulates the production of erythropoietin or, alternatively, whether a decrease in erythropoietin contributes to the induction of anemia. Methods: Two mouse models of colitis were used in this study: (1) acute 6-day ingestion of dextran sodium sulfate and (2) T-cell transfer into lymphopenic recipient mice. Measurements included indices of colitis severity, hematocrit, blood hemoglobin, plasma erythropoietin, serum iron concentration, plasma iron-binding capacities, transferrin saturation, and tissue iron concentrations. Results: Both models of colitis induced significant decreases in hematocrit, blood hemoglobin, and transferrin saturation, with the spleen and liver showing a decrease in iron content in the T-cell transfer model. Additionally, both models of colitis demonstrated significant increases in plasma erythropoietin and plasma iron-binding capacities. Conclusions: The measurements of iron, whether in acute (dextran sodium sulfate) or chronic (T-cell transfer) models of colitis, were generally consistent with iron-deficient anemia, with large increases in erythropoietin indicative of tissue hypoxia. These changes in animal models of colitis are similar to those found in human IBD.
    No preview · Article · Apr 2013 · Inflammatory Bowel Diseases
  • Matthew B Grisham
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    ABSTRACT: Intracellular generation of reactive oxygen species (ROS) is an inescapable consequence of aerobic metabolism. Although some of these oxygen-derived metabolites are well-documented mediators of cell and tissue damage, others have been shown to be crucial for cell survival and homeostasis. One ROS that has been identified as a major second messenger in redox signaling is hydrogen peroxide (H(2)O(2)). This small, membrane-permeable oxidant is produced transiently in physiological (nontoxic) amounts by a variety of different enzymes residing within different subcellular compartments and organelles. There is an accumulating literature demonstrating that the reversible, H(2)O(2)-mediated oxidation of different signaling proteins is an important posttranslational mechanism that regulates a number of different biological processes including cell proliferation, differentiation, motility and apoptosis. Although several, well-characterized methods have been developed to quantify the generation of extracellular H(2)O(2), the ability to unequivocally detect and quantify this important signaling molecule within living cells has been relatively limited. Fortunately, a great deal of progress has been made over the past few years in developing H(2)O(2)-selective probes that are capable of detecting physiological levels this signaling molecule. This overview presents a critical evaluation of the established as well as the more recently developed methods to detect and quantify extracellular and intracellular H(2)O(2) produced by living cells.
    No preview · Article · Feb 2013 · Comparative biochemistry and physiology. Part A, Molecular & integrative physiology
  • D. Neil Granger · Christopher G. Kevil · Matthew B. Grisham

    No preview · Chapter · Dec 2012
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    ABSTRACT: Introduction: We have previously demonstrated that adoptive transfer of naïve CD4+ T cells devoid of lymphocyte function-associated antigen-1-deficient (LFA-1; CD11a/CD18) into recombination activating gene-1 (RAG-1) deficient (RAG-/-) mice fails to induce chronic colitis whereas transfer of wild type (WT) T-cells induces unrelenting and chronic disease. Methods: The objectives of this study were to assess the role of lymphocyte function-associated antigen-1 (LFA-1) in enteric antigen (EAg)-induced activation of T cells in vitro and in vivo and to define the importance of this integrin in promoting trafficking of T cells to the mesenteric lymph nodes (MLNs) and colon. Results: We found that EAg-pulsed dendritic cells (DCs) induced proliferation of LFA-1-deficient (CD11a -/-) CD4+ T cells that was very similar to that induced using WT T cells, suggesting that LFA-1 is not required for activation/ proliferation of T cells in vitro. Coculture of WT or CD11a-/- T cells with EAg-pulsed DCs induced the generation of similar amounts of interferon-gamma, interleukin (IL)-4, and IL-10, whereas IL-17A production was reduced ≈2-fold in cocultures with CD11a-/- T cells. Short-term (20-22 hours) trafficking studies demonstrated that while both WT and CD11a -/- T cells migrated equally well into the spleen, liver, lungs, small intestine, cecum, and colon, trafficking of CD11a-/- T cells to the MLNs was reduced by 50% when compared to WT T cells. When the observation period was extended to 3-7 days posttransfer, we observed ≈2-3-fold more WT T cells within the MLNs and colon than CD11a-/- T cells, whereas T-cell proliferation (as measured by CFSE dilution) was comparable in both populations. Conclusions: Taken together, our data suggest that LFA-1 is not required for EAg-induced activation of CD4+ T cells in vitro or in vivo but is required for trafficking of T cells to the MLNs and homing of colitogenic effector cells to the colon where they initiate chronic gut inflammation.
    Full-text · Article · Dec 2012 · Inflammatory Bowel Diseases
  • Kai Fang · Matthew Grisham · Christopher Kevil

    No preview · Article · Dec 2012 · Inflammatory Bowel Diseases
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    ABSTRACT: Background & aims: Signaling lymphocyte activation molecule (Slamf)1 is a co-stimulatory receptor on T cells and regulates cytokine production by macrophages and dendritic cells. Slamf1 regulates microbicidal mechanisms in macrophages, therefore we investigated whether the receptor affects development of colitis in mice. Methods: We transferred CD45RB(hi) CD4(+) T cells into Rag(-/-) or Slamf1(-/-)Rag(-/-) mice to induce colitis. We also induced colitis by injecting mice with an antibody that activates CD40. We determined the severity of enterocolitis based on disease activity index, histology scores, and levels of cytokine production, and assessed the effects of antibodies against Slamf1 on colitis induction. We quantified migration of monocytes and macrophage to inflamed tissues upon induction of colitis or thioglycollate-induced peritonitis and in response to tumor necrosis factor-α in an air-pouch model of leukocyte migration. Results: Colitis was reduced in Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after transfer of CD45RB(hi) CD4(+) T cells or administration of the CD40 agonist. The numbers of monocytes and macrophages were reduced in inflamed tissues of Slamf1(-/-)Rag(-/-) mice, compared with Rag(-/-) mice, after induction of colitis and other inflammatory disorders. An antibody that inhibited Slamf1 reduced the level of enterocolitis in Rag(-/-) mice. Conclusions: Slamf1 contributes to the development of colitis in mice. It appears to indirectly regulate the appearance of monocytes and macrophages in inflamed intestinal tissues. Antibodies that inhibit Slamf1 reduce colitis in mice, so human SLAMF1 might be a therapeutic target for inflammatory bowel disease.
    No preview · Article · Sep 2012 · Gastroenterology
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    Kai Fang · Songlin Zhang · John Glawe · Matthew B Grisham · Christopher G Kevil
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    ABSTRACT: T cells critically regulate inflammatory bowel disease (IBD), with T-cell-dependent experimental colitis models gaining favor in identifying potential pathogenic mechanisms; yet limited understanding of specific pathogenic molecules or pathways still exists. In this study we sought to identify changes in whole genome expression profiles using the CD4CD45Rbhi T-cell transfer colitis model compared to genome expression differences from Crohn's disease (CD) tissue specimens. Colon tissue was used for histopathological and genome expression profiling analysis at 0, 2, 4, or 6 weeks after adoptive T-cell transfer. We identified 1775 genes that were significantly altered during disease progression, with 361 being progressively downregulated and 341 progressively upregulated. Gene expression changes were validated by quantitative real-time polymerase chain reaction (qRT-PCR), confirming genome expression analysis data. Differentially expressed genes were clearly related to inflammation/immune responses but also strongly associated with metabolic, chemokine signaling, Jak-STAT signaling, and angiogenesis pathways. Ingenuity network analysis revealed 25 unique network associations that were associated with functions such as antigen presentation, cell morphology, cell-to-cell signaling and interaction, as well as nervous system development and function. Moreover, many of these genes and pathways were similarly identified in CD specimens. These findings reveal novel, complex, and dynamic changes in gene expression that may provide useful targets for future therapeutic approaches.
    Full-text · Article · Aug 2012 · Inflammatory Bowel Diseases
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    ABSTRACT: Active episodes of the inflammatory bowel diseases are associated with the infiltration of large numbers of myeloid cells including neutrophils, monocytes, and macrophages. The objective of this study was to systematically characterize and define the different populations of myeloid cells generated in a mouse model of chronic gut inflammation. Using the T cell transfer model of chronic colitis, we found that induction of disease was associated with enhanced production of myelopoietic cytokines (IL-17 and G-CSF), increased production of neutrophils and monocytes, and infiltration of large numbers of myeloid cells into the mesenteric lymph nodes (MLNs) and colon. Detailed characterization of these myeloid cells revealed three major populations including Mac-1(+)Ly6C(high)Gr-1(low/neg) cells (monocytes), Mac-1(+)Ly6C(int)Gr-1(+) cells (neutrophils), and Mac-1(+)Ly6C(low/neg)Gr-1(low/neg) leukocytes (macrophages, dendritic cells, and eosinophils). In addition, we observed enhanced surface expression of MHC class II and CD86 on neutrophils isolated from the inflamed colon when compared with neutrophils obtained from the blood, the MLNs, and the spleen of colitic mice. Furthermore, we found that colonic neutrophils had acquired APC function that enabled these granulocytes to induce proliferation of OVA-specific CD4(+) T cells in an Ag- and MHC class II-dependent manner. Finally, we observed a synergistic increase in proinflammatory cytokine and chemokine production following coculture of T cells with neutrophils in vitro. Taken together, our data suggest that extravasated neutrophils acquire APC function within the inflamed bowel where they may perpetuate chronic gut inflammation by inducing T cell activation and proliferation as well as by enhancing production of proinflammatory mediators.
    Full-text · Article · Jan 2012 · The Journal of Immunology

Publication Stats

20k Citations
2,025.57 Total Impact Points

Institutions

  • 2013-2015
    • Texas Tech University Health Sciences Center
      • Department of Microbiology and Immunology
      El Paso, Texas, United States
  • 2012-2014
    • Texas Tech University
      Lubbock, Texas, United States
  • 1999-2012
    • Louisiana State University Health Sciences Center Shreveport
      • • School of Medicine
      • • Department of Pathology
      • • Department of Pediatrics
      Shreveport, Louisiana, United States
    • Albany Medical College
      • Center for Cardiovascular Sciences
      Albany, New York, United States
    • Thomas Jefferson University
      Filadelfia, Pennsylvania, United States
  • 1988-2012
    • Louisiana State University in Shreveport
      Shreveport, Louisiana, United States
    • University of Missouri
      • Department of Biomedical Sciences
      Columbia, MO, United States
  • 1996-2008
    • Louisiana State University
      Baton Rouge, Louisiana, United States
    • National Heart, Lung, and Blood Institute
      베서스다, Maryland, United States
    • University of Wyoming
      • Department of Chemistry
      Laramie, Wyoming, United States
  • 2006
    • University of South Carolina
      Columbia, South Carolina, United States
  • 2004
    • National Institutes of Health
      • Branch of Radiation Biology
      Bethesda, MD, United States
  • 2002
    • Duke University
      Durham, North Carolina, United States
  • 2001
    • Keio University
      • Department of Surgery
      Edo, Tōkyō, Japan
  • 1999-2001
    • National Cancer Institute (USA)
      • Radiation Biology Branch
      Maryland, United States
  • 2000
    • Overton Brooks VA Medical Center
      Shreveport, Louisiana, United States
    • Shinshu University
      Shonai, Nagano, Japan
  • 1990-2000
    • LSU Medical Center
      • • Department of Physiology
      • • Department of Surgery
      Shreveport, Louisiana, United States
  • 1995
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Medicine
      New Orleans, Louisiana, United States
  • 1985-1987
    • University of South Alabama
      • • Department of Physiology
      • • College of Medicine
      Mobile, Alabama, United States
  • 1984-1986
    • St. Jude Children's Research Hospital
      • Department of Biochemistry
      Memphis, Tennessee, United States