Immunohistological analysis of macrophages in the central nervous system of Lewis rats with acute experimental allergic encephalomyelitis

Polman, Chris H.; Dijkstra, C.D.; Sminia, T.; Koetsier, J.C.

doi:10.1016/0165-5728(86)90005-6

Cited by 102 publications

(33 citation statements)

References 20 publications

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“…6b, animals that received their first dose of INCB3344 7 days after immunization still showed significant inhibition of disease as manifested by suppression of the apparent disease incidence (vehicle 100% vs INCB3344 64%) as well as severity (maximum mean clinical score vehicle 2.57 Ϯ 0.78 vs INCB3344 1.43 Ϯ 1.22). Dosing was initiated on day 7 when histological evidence of disease is present but few animals are presenting clinical signs (28). The data clearly show that CCR2 antagonism therapeutically can halt the progression of EAE.…”

Section: Ccr2mentioning

confidence: 95%

Discovery and Pharmacological Characterization of a Novel Rodent-Active CCR2 Antagonist, INCB3344

Brodmerkel

Huber

Covington

et al. 2005

The Journal of Immunology

172

144

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This report describes the characterization of INCB3344, a novel, potent and selective small molecule antagonist of the mouse CCR2 receptor. The lack of rodent cross-reactivity inherent in the small molecule CCR2 antagonists discovered to date has precluded pharmacological studies of antagonists of this receptor and its therapeutic relevance. In vitro, INCB3344 inhibits the binding of CCL2 to mouse monocytes with nanomolar potency (IC50 = 10 nM) and displays dose-dependent inhibition of CCL2-mediated functional responses such as ERK phosphorylation and chemotaxis with similar potency. Against a panel of G protein-coupled receptors that includes other CC chemokine receptors, INCB3344 is at least 100-fold selective for CCR2. INCB3344 possesses good oral bioavailability and systemic exposure in rodents that allows in vivo pharmacological studies. INCB3344 treatment results in a dose-dependent inhibition of macrophage influx in a mouse model of delayed-type hypersensitivity. The histopathological analysis of tissues from the delayed-type hypersensitivity model demonstrates that inhibition of CCR2 leads to a substantial reduction in tissue inflammation, suggesting that macrophages play an orchestrating role in immune-based inflammatory reactions. These results led to the investigation of INCB3344 in inflammatory disease models. We demonstrate that therapeutic dosing of INCB3344 significantly reduces disease in mice subjected to experimental autoimmune encephalomyelitis, a model of multiple sclerosis, as well as a rat model of inflammatory arthritis. In summary, we present the first report on the pharmacological characterization of a selective, potent and rodent-active small molecule CCR2 antagonist. These data support targeting this receptor for the treatment of chronic inflammatory diseases.

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Section: Ccr2mentioning

confidence: 95%

Discovery and Pharmacological Characterization of a Novel Rodent-Active CCR2 Antagonist, INCB3344

Brodmerkel

Huber

Covington

et al. 2005

The Journal of Immunology

172

144

View full text Add to dashboard Cite

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“…Polman et al (1986) found la + lymphocytes in the spinal cord of rats with EAE induced by inoculation with spinal cord tissue. Lyman et al (1989) identified la + lymphocytes in cells extracted from the spinal cord of rats with MBP-EAE.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD45RC and Ia antigen in the spinal cord in acute experimental allergic encephalomyelitis: An immunocytochemical and flow cytometric study

McCombe

Fordyce

Jersey

et al. 1992

Journal of the Neurological Sciences

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We performed immunocytochemical studies to analyze the inflammatory infiltrate and major histocompatibility complex class II (Ia) antigen expression in the spinal cord of Lewis rats with acute experimental allergic encephalomyelitis (EAE) induced by inoculation with myelin basic protein and adjuvants. Using antibodies to lymphocyte markers and other monoclonal antibodies we found that during clinical episodes the inflammatory infiltrate was chiefly composed of T lymphocytes and macrophages. The majority of cells in the inflammatory infiltrate were stained by the W3/25 antibody to CD4 and a proportion was stained by OX22 which labels the high molecular weight form of the leucocyte common antigen (CD45RC). CDB+ T cells were sparse and B cells were not detected. There was minimal staining with the OX39 antibody to the interleukin-2 receptor. Presumptive microglia, identified by their dendritic morphology, expressed Ia antigen during the clinical episodes and after recovery. The prominence of Ia antigen expression after recovery could indicate that this la expression was associated with downregulation of the encephalitogenic immune response. We also performed flow cytometry studies on cells extracted from the spinal cord of rats before and during attacks of EAE. With flow cytometry, we found that in established disease a mean of 83(SD, 23)% of CD2+ cells were CD4+, and a mean of 27(SD, 12)% of CD2+ cells were CD45RC+. In rats sampled on the first day of signs, a mean of 43(SD, 22)% of CD2+ cells were CD45RC+. In the cells extracted from the spinal cord of rats with established disease a mean of 47(SD, 32)% of macrophages were CD45RC+. Our study has combined an immunocytochemical assessment of tissue sections with quantitative flow cytometry assessment of cells extracted from the spinal cord of rats with acute EAE. We have shown that the majority of T lymphocytes in the spinal cord are CD45RC − . We have also found prominent Ia expression on dendritic cells in acute EAE and after clinical recovery.

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“…Intermediate levels are expressed on 50 to 90% of resident bone marrow macrophages, and low but detectable levels are found for Kupffer cells, red pulp macrophages, and alveolar macrophages (9,10). Besides expression on subsets of resident tissue macrophages, Sn is expressed at high levels on inflammatory macrophages in rheumatoid arthritis, atherosclerosis (16), experimental autoimmune uveoretinitis (17), experimental allergic encephalomyelitis (37), and nephritis (5) and on macrophages that infiltrate human breast tumors (35). Very recent reports show that Sn can also be expressed by certain dendric cells (2,20) and on inflammatory blood monocytes following human immunodeficiency virus infection (39).…”

mentioning

confidence: 99%

Sialoadhesin-Deficient Mice Exhibit Subtle Changes in B- and T-Cell Populations and Reduced Immunoglobulin M Levels

Oetke

Vinson

Jones

et al. 2006

Molecular and Cellular Biology

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Sialoadhesin (Sn, also called Siglec-1 or CD169) is a transmembrane receptor and the prototypic member of the Siglec family of sialic acid binding immunoglobulin-like lectins. It is expressed on specialized subsets of resident macrophages in hematopoietic and lymphoid tissues and on inflammatory macrophages. In order to investigate its function, we generated Sn-deficient mice and confirmed that these mice are true nulls by fluorescence-activated cell sorter analysis and immunohistochemistry. Mice deficient in Sn were viable and fertile and showed no developmental abnormalities. Analysis of cell populations revealed no differences in bone marrow, peritoneal cavity, and thymus, but there was a small increase in CD8 T cells and a decrease in B220-positive cells in spleens and lymph nodes of Sn-deficient mice. Furthermore, in spleen there was a slight decrease in follicular B cells with an increase in numbers of marginal zone B cells. B-and T-cell maturation as well as responses to stimulation with thioglycolate were only slightly affected by Sn deficiency. Immunoglobulin titers in Sn-deficient mice were significantly decreased for immunoglobulin M (IgM) but similar for IgG subclasses. These results suggest a role for sialoadhesin in regulating cells of the immune system rather than in influencing steady-state hematopoiesis.

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Immunohistological analysis of macrophages in the central nervous system of Lewis rats with acute experimental allergic encephalomyelitis

Cited by 102 publications

References 20 publications

Discovery and Pharmacological Characterization of a Novel Rodent-Active CCR2 Antagonist, INCB3344

Discovery and Pharmacological Characterization of a Novel Rodent-Active CCR2 Antagonist, INCB3344

Expression of CD45RC and Ia antigen in the spinal cord in acute experimental allergic encephalomyelitis: An immunocytochemical and flow cytometric study

Sialoadhesin-Deficient Mice Exhibit Subtle Changes in B- and T-Cell Populations and Reduced Immunoglobulin M Levels

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