Showing papers by "Matthew B. Grisham published in 2012"

Acquisition of Antigen-Presenting Functions by Neutrophils Isolated from Mice with Chronic Colitis

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.

Temporal genome expression profile analysis during t-cell-mediated colitis: identification of novel targets and pathways.

Abstract: T cells critically regulate 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 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 1,775 genes that were significantly altered during disease progression with 361 being progressively down regulated and 341 progressively up regulated. Gene expression changes were validated by 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 Crohn's disease specimens. These findings reveal novel, complex, and dynamic changes in gene expression that may provide useful targets for future therapeutic approaches.

Recruitment of Inflammatory and Immune Cells in the Gut: Physiology and Pathophysiology

Abstract: The recruitment of leukocytes to most tissues is generally associated with tissue injury and/or inflammation. However, the GI tract is unique in that the healthy gut exists in a state of controlled inflammation, wherein there is a constant trafficking of leukocytes to both lymphoid and non-lymphoid regions of the intestinal mucosa. Many GI diseases and disorders are characterized by a more pronounced and persistent recruitment of leukocytes into gut tissue, coupled with dysregulated activation of the infiltrating cells, which ultimately contributes to tissue injury and organ dysfunction. The overall objective of this chapter is to present the current understanding of the mediators and mechanisms that regulate the recruitment and activation of innate and adaptive immune cells to the healthy and inflamed intestine.

Role of LFA‐1 in the activation and trafficking of T cells: Implications in the induction of chronic colitis

Abstract: Introduction: We have previously demonstrated that adoptive transfer of naive 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. (Inflamm Bowel Dis 2012;)

Chapter 79 – Recruitment of Inflammatory and Immune Cells in the Gut: Physiology and Pathophysiology

Abstract: The recruitment of leukocytes to most tissues is generally associated with tissue injury and/or inflammation. However, the GI tract is unique in that the healthy gut exists in a state of controlled inflammation, wherein there is a constant trafficking of leukocytes to both lymphoid and non-lymphoid regions of the intestinal mucosa. Many GI diseases and disorders are characterized by a more pronounced and persistent recruitment of leukocytes into gut tissue, coupled with dysregulated activation of the infiltrating cells, which ultimately contributes to tissue injury and organ dysfunction. The overall objective of this chapter is to present the current understanding of the mediators and mechanisms that regulate the recruitment and activation of innate and adaptive immune cells to the healthy and inflamed intestine.

Preclinical Studies Using Mouse Models of Inflammatory Bowel Disease

Abstract: Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose–responses, and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. It is becoming increasingly appreciated that the failure to translate therapeutic efficacy from bench to bedside may be due, in part, to selection of an animal model that may not recapitulate the immunopathologic features of the human disease under investigation. This is especially true for preclinical investigations using mouse models of the inflammatory bowel diseases (IBD; Crohn’s disease, ulcerative colitis). One potential strategy for improving our ability to discover new therapeutics that may have a reasonable chance of success in clinical trials is to identify the most immunologically relevant mouse models of human IBD. This chapter presents a critical evaluation of the different mouse models of IBD and discusses their utility in preclinical studies.