The Role of Chemokines in Oral Tolerance.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75554/1/j.1749-6632.1996.tb21122.x.pd

Respiratory syncytial virus infection modifies and accelerates pulmonary disease via DC activation and migration

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141386/1/jlb0005.pd

The role of egg antigens, cytokines in granuloma formation in murine schistosomiasis mansoni

The induction of granuloma formation by soluble egg antigens (SEA) of Schistosoma mansoni is accompanied by T cell-mediated lymphokine production that regulates the intensity of the response. In the present study we have examined the ability of SDS-PAGE fractioned SEA proteins to elicit granulomas and lymphokine production in infected and egg-immunized mice. At the acute stage of infection SEA fractions ( 200 kD) that elicited pulmonary granulomas also elicited IL-2, IL-4 lymphokine production. At the chronic stage a diminished number of fractions (60-66, 70-90, 93-125, and > 200 kD) were able to elicit granulomas with an overall decrease in IL-2, IL-4 production. Granulomas were elicited by larval-egg crossreactive and egg-specific fractions at both the acute and chronic stage of the infection. Examination of lymphokine production from egg-immunized mice demonstrated that as early as 4 days IL-2 was produced by spleen cells stimulated with 200 kD fractions. By 16 days, IL-2production was envoked by 8 of 9 fractions. IL-4 production at 4 days in response to all fractions was minimal while at 16 days IL-4 was elicited with the 200 kD fractions. The present study reveals differences in the range of SEA fractions able to elicit granulomas and IL-2, IL-4 production between acute and chronic stages of infection. Additionally, this study demonstrates sequential (IL-2 followed by IL-4) lymphokine production during the primary egg antigen response

Role of CC chemokine CCL6/C10 as a monocyte chemoattractant in a murine acute peritonitis.

The aim of this study was to determine the role of CC chemokine CCL6/C10 in acute inflammation. Intraperitoneal injection of thioglycollate increased peritoneal CCL6, which peaked at 4 h and remained elevated at 48 h. Neutralization of CCL6 significantly inhibited the macrophage infiltration (34-48% reduction), but not other cell types, without decreasing the other CC chemokines known to attract monocytes/macrophages. CCL6 was expressed in peripheral eosinophils and elicited macrophages, but not in elicited neutrophils. Peritoneal CCL6 level was not decreased in granulocyte-depleted mice where eosinophil influx was significantly impaired. Thus, CCL6 appears to contribute to the macrophage infiltration that is independent of other CC chemokines. Eosinophils pre-store CCL6, but do not release CCL6 in the peritoneum in this model of inflammation

Regulation of Immunity to Respiratory Syncytial Virus by Dendritic Cells, Toll-Like Receptors, and Notch

The activation and maintenance of pulmonary viral disease is regulated at multiple levels and determined by the early innate response to the pathogenic stimuli. Subsequent activation events that rely directly and indirectly on the virus itself can alter the development and severity of the ensuing immunopathologic responses. In the present review we outline several interconnected mechanisms that rely on the early recognition of viral nucleic acid for the most appropriate anti-viral immune responses, including TLRs and Notch activation in DCs and T cells. Deviation or persistence of the immune response to respiratory viruses may impact significantly on the severity of the responses. While these mechanisms are likely similar in most respiratory viral infections, this review will focus on findings with respiratory syncytial virus (RSV) infections.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63262/1/vim.2007.0110.pd

Stem cell factor and IgE-stimulated murine mast cells produce chemokines (CCL2, CCL17, CCL22) and express chemokine receptors

Objective and design: In the present study we investigated the effect of SCF and/or IgE on histamine, TNF- α and chemokines released from bone marrow-derived mast cells (BMMC) as well as chemokine receptor expression.¶ Material and methods: BMMC were derived from femoral bone marrow of CBA/J mice. The purity of BMMC was >98%percnt; after 3 weeks. BMMC (2.5 × 10 6 cells/well) were incubated in the presence or absence of either SCF, IgE plus DNP or a combination of SCF and IgE for 6 and 18 h. Cell-free supernatants were recovered to measure CC chemokines, TNF- α and histamine release utilizing ELISA assays. CC chemokine family receptors were detected by RT-PCR analysis, and confirmed using functional chemotactic assays.¶ Results: Histamine levels were comparable between SCF and IgE stimulated cells, whereas TNF- α production was significantly greater after IgE compared to SCF stimulation. SCF and/or IgE-stimulated BMMC released CC chemokines, CCL22 (MDC), CCL17 (TARC) and CCL2 (MCP-1). Increased mRNA expression of CCR1, CCR2, CCR3, and CCR5 was detected in SCF and IgE-stimulated BMMCs. Functional chemotactic assays confirmed the expression data.¶ Conclusion: SCF and IgE can up-regulate the expression of chemokines and chemokine receptors on mast cells. Thus, SCF may play a significant role in their activation and inflammation during allergic responses.¶Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41824/1/11-50-3-168_10500168.pd

Eosinophil recruitment into sites of delayed‐type hypersensitivity reactions in mice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142239/1/jlb0353.pd

The chemokine receptor CCR6 is an important component of the innate immune response

In our initial studies we found that naÏve CCR6-deficient (CCR6 –/– ) C57BL/6 mice possessed significantly lower number of both F4/80 + macrophages and dendritic cells (DC), but higher number of B cells in the peritoneal cavity, as compared to naÏve wild type (WT) controls. Furthermore, peritoneal macrophages isolated from CCR6 –/– mice expressed significantly lower levels of inflammatory cytokines and nitric oxide following lipopolysaccharide (LPS)stimulation, as compared to WT macrophages. In a severe experimental peritonitis model induced by cecal ligation and puncture (CLP), CCR6 –/– mice were protected when compared with WT controls. At 24 h following the induction of peritonitis, CCR6 –/– mice exhibited significantly lower levels of inflammatory cytokines/chemokines in both the peritoneal cavity and blood. Interestingly, DC recruitment into the peritoneal cavity was impaired in CCR6 –/– mice during the evolution of CLP-induced peritonitis. Peritoneal macrophages isolated from surviving CCR6 –/– mice 3 days after CLP-induced peritonitis exhibited an enhanced LPS response compared with similarly treated WT peritoneal macrophages. These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56112/1/2487_ftp.pd

The role of ILâ 5 in bleomycinâ induced pulmonary fibrosis

Eosinophils are known to express cytokines capable of promoting fibrosis. Interleukinâ 5 (ILâ 5) is important in regulating eosinophilopoiesis, eosinophil recruitment and activation. Lung ILâ 5 expression is elevated in pulmonary fibrosis, wherein the eosinophil is a primary source of fibrogenic cytokines. To determine the role of ILâ 5 in pulmonary fibrosis, the effects of antiâ ILâ 5 antibody were investigated in a model of bleomycinâ induced pulmonary fibrosis. Fibrosis was induced in mice by endotracheal bleomycin treatment. Animals were also treated with either antiâ ILâ 5 antibody or control IgG. Lungs were then analyzed for fibrosis, eosinophil influx, chemotactic activity, and cytokine expression. The results show that a primary chemotactic activity at the height of eosinophil recruitment is ILâ 5. Furthermore, antiâ ILâ 5 antibody caused significant reduction in lung eosinophilia, cytokine expression, and fibrosis. These findings taken together suggest an important role for ILâ 5 in pulmonary fibrosis via its ability to regulate eosinophilic inflammation, and thus eosinophilâ dependent fibrogenic cytokine production. J. Leukoc. Biol. 64: 657â 666; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141191/1/jlb0657.pd