Abstract We investigated the immune responses in mice lacking CCR2, CCR5, or macrophage inflammatory protein-1α (MIP-1α), a ligand for CCR5, in two situations: following T cell stimulation or after challenge with Leishmania donovani, an intracellular microbe whose control is dependent on a Th1 immune response. Mice deficient in CCR5, MIP-1α, or CCR2 had reduced IFN-γ responses following ligation of the TCR. Reduced IFN-γ responses following PMA and ionomycin were also observed in CD8+ T cells of CCR5−/− and CCR2−/− mice. During the early phases of infection, all three knockout mice had low Ag-specific IFN-γ responses. However, this reduced IFN-γ response was overcome during a state of persistent Ag stimulation (chronic infection), and was not associated with an adverse parasitologic outcome in any of the gene-targeted mouse strains. To the contrary, during the late phase of infection, an exaggerated Ag-specific IFN-γ response was evident in CCR5−/− and MIP-1α−/− mice, and this correlated with an enhanced control of parasite replication. Although granuloma formation was abnormal in each of the knockout mice, there was no correlation between the number or architecture of the granulomas and parasite burden. Collectively, these findings indicate an important role for CCR5, MIP-1α, and CCR2 in granulomatous inflammation, and that CCR5 and MIP-1α, possibly acting through CCR5, might play a deleterious role in the outcome of chronic L. donovani infection. Our data also suggest that there might be cross-talk between TCR and chemokine receptor signaling pathways.

CCR2

CC chemokine receptors

Macrophage inflammatory protein

Knockout mouse

10.4049/jimmunol.163.10.5519

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Citations (133)

Options for Improving Timely Access to Care Reporting in California

Jeanne S. Ringel Glenn Melnick Claude Messan Setodji Robert L. Reddick Susan M. Paddock

The state of California has taken the lead in developing metrics, standards, and a methodology for collecting the needed data for monitoring timely access to health care, but health plans have faced numerous challenges in collecting and reporting this information. This report focuses on specific concerns with the methodology; the authors use a multipronged approach to describe and document these issues and identify and assess potential solutions.

Data access

Source

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HDL metabolism and atherogenesis in genetically modified mice

Developments in cardiovascular medicine (1995)

Nobuo Maeda S. H. Zhang Robert L. Reddick

Candidate gene

10.1007/978-94-011-6585-3_7

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Regulation of Calreticulin Expression during Induction of Differentiation in Human Myeloid Cells

Journal of Biological Chemistry (2002)

Robert A. Clark Senlin Li Doran W. Pearson Kevin G. Leidal Joshua R. Clark

Calnexin

Ionomycin

Thapsigargin

10.1074/jbc.m205269200

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Citations (23)

Ultrastructural organization of the Reed-Sternberg cell: its resemblance to cells of the monocyte-macrophage system.

PubMed (1980)

Stephen C. Peiper Leonard B. Kahn D W Ross Robert L. Reddick

A dichotomy exists in the characterizations of the histogenesis of Hodgkin's disease. The Reed-Sternberg cell has been shown to possess functional properties both of lymphocytes and of mononuclear phagocytes. The majority of ultrastructural studies support the lymphocytic origin although a conflicting report describes some features of "histiocytic" cells [9]. In our study of four cases of Hodgkin's disease, the Reed-Sternberg cells contained a well-developed Golgi, moderate numbers of free polyribosomes and smooth and rough endoplasmic reticulum, variable numbers of lysosomes, lipid droplets, glycogen, fibrillar bodies, and irregular cytoplasmic processes. The number, size, and organization of cytoplasmic organelles are more consistent with a mononuclear phagocyte than a transformed lymphocyte and are similar to those seen in monoblastic leukemias. These findings support the concept of the derivation of the Reed-Sternberg cell from a monocyte-macrophage.

Mononuclear phagocyte system

Histogenesis

Organelle

Monocyte

Polysome

Lipid droplet

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A novel highly potent trivalent TGF-β receptor trap inhibits early-stage tumorigenesis and tumor cell invasion in murine Pten-deficient prostate glands

Oncotarget (2016)

Tai Qin Lindsey Barron Lu Xia Haojie Huang Maria M. Villarreal

The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.

Tumor progression

10.18632/oncotarget.13343

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Citations (32)