Polymorphonuclear Leukocyte Chemotactic Activity in Rabbit Serum and Guinea Pig Serum Treated with Immune Complexes: Evidence for C5a as the Major Chemotactic Factor

Snyderman, Ralph; Phillips, Jean K.; Mergenhagen, Stephan E.

doi:10.1128/iai.1.6.521-525.1970

Cited by 148 publications

(21 citation statements)

References 15 publications

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“…DSS colitis is characterized by massive infiltration by neutrophils and macrophages (Stevceva et al ., ), and C5a is a known chemoattractant for these cell types (Snyderman et al ., 1970; 1975). Consequently, we sought to determine whether protection by PMX205 was associated with changes in the numbers of either leukocyte type.…”

Section: Resultsmentioning

confidence: 99%

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

Jain

Woodruff

Stadnyk

2012

British J Pharmacology

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BACKGROUND AND PURPOSEAnti-complement therapies have not been advanced for treating the inflammatory bowel diseases (IBDs) despite a growing body of evidence that blocking C5a protects against induced colitis in rodents. The purpose of this study was to further build on this evidence by examining the efficacy, mechanism and specificity of a potent, non-competitive and orally active C5a receptor (CD88) antagonist, PMX205, in the dextran sulphate sodium (DSS) model of murine innate colitis. EXPERIMENTAL APPROACHMice with DSS added to their drinking water were orally administered 100 or 200 mg day -1 PMX205 in prophylactic and therapeutic regimens. Clinical illness, colon histology and local generation of inflammatory mediators were measured to evaluate the impact of PMX205 on disease. KEY RESULTSPMX205 significantly prevented DSS-induced colon inflammation in both regimens, associated with lower pro-inflammatory cytokine production and nitrotyrosine staining in colon sections. Additionally, the levels of anti-inflammatory cytokines IL-4 and IL-10 were increased. PMX205 had no significant effect on C5a levels. The beneficial effect of PMX205 was seen in two strains of mice of differing sensitivities to DSS inflammation, but was inactive in mice lacking CD88. CONCLUSIONS AND IMPLICATIONSPharmacological inhibition of C5a activity by PMX205 is efficacious in preventing DSS-induced colitis, providing further evidence that targeting CD88 in IBD patients could be a valuable therapeutic option.

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Section: Resultsmentioning

confidence: 99%

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

Jain

Woodruff

Stadnyk

2012

British J Pharmacology

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“…The complement activation-dependent anaphylatoxins, C3a and C5a, are mediators of leukocyte activation and migration (74)(75)(76)(77)(78). Work determining the importance of these anaphylatoxins in the field of transplant rejection has elucidated effects of direct activation of lymphocytes and endothelium, inducing proliferation and changes in vascular permeability, respectively (79)(80)(81)(82)(83)(84).…”

Section: Discussionmentioning

confidence: 99%

An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA

Thomas

Valenzuela

Gjertson

et al. 2015

American Journal of Transplantation

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Antibody-mediated rejection (AMR) of solid organ transplants (SOT) is characterized by damage triggered by donor-specific antibodies (DSA) binding donor Class I and II HLA (HLA-I and HLA-II) expressed on endothelial cells. While F(ab′)2 portions of DSA cause cellular activation and proliferation, Fc regions activate the classical complement cascade, resulting in complement deposition and leukocyte recruitment, both hallmark features of AMR. We characterized the ability of an anti-C1s monoclonal antibody, TNT003, to inhibit HLA antibody (HLA-Ab)-induced complement activation. Complement deposition induced by HLA-Ab was evaluated using novel cell- and bead-based assays. Human aortic endothelial cells (HAEC) were cultured with HLA-Ab and human complement; production of activated complement proteins was measured by flow cytometry. Additionally, C3d deposition was measured on single antigen beads (SAB) mixed with HLA-Ab and human complement. TNT003 inhibited HLA-Ab mediated complement deposition on HAEC in a concentration-dependent manner; C3a, C4a and C5a anaphylatoxin production was also diminished by TNT003. Finally, TNT003 blocked C3d deposition induced by Class I (HLAI-Ab)- and Class II (HLAII-Ab)-specific antibodies on SAB. These data suggest TNT003 may be useful for modulating the effects of DSA, as TNT003 inhibits complement deposition and split product formation generated by HLA-I/II-Ab in vitro.

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“…Washed cells were suspended in Gey's balanced salt solution containing 0.1% bovine serum albumin (BSA) in 0.015 M HEPES buffer at pH 7.4, at a concentration of 8-11 x 106 cells/ml. Chemotaxis was routinely measured in modified Boyden chambers as described (44). Cell viability was determined by trypan blue exclusion.…”

Section: Leukocyte Preparationmentioning

confidence: 99%

Stimulation of tubulin tyrosinolation in rabbit leukocytes evoked by the chemoattractant formyl-methionyl-leucyl-phenylalanine.

Nath¹,

Flavin²,

Schiffmann³

1981

The Journal of Cell Biology

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Cellular tubulin is subject to a posttranslational modification involving the reversible addition of tyrosine through peptide linkage to the C-terminal glutamate of the a-chain . The synthetic peptide chemoattractant, N-formyl-methionyl-leucyl-phenylalanine, causes a specific, dose-dependent stimulation of tubulin tyrosinolation in rabbit leukocytes. This stimulation is prevented by carbobenzoxy-phenyl alanyl-meth ion ine, benzoyl-tyrosine ethylester, and nordihydroguaiaretic acid, which are all inhibitors of chemotaxis presumed to act via membrane-associated events . The combination of 3-deazaadenosine and homocysteine thiolactone, which inhibits phospholipid methylation, and quinacrine, an inhibitor of phospholipase A2 , also abolishes the response to the peptide . Colchicine, however, which causes a marked disassembly of cellular microtubules in these cells and also inhibits chemotaxis, does not have any inhibitory effect on the basal or peptide-stimulated rate of tubulin tyrosinolation . In contrast, taxol, a microtubule-stabilizing agent, has an inhibitory effect on both the basal and peptide-stimulated tyrosine incorporation . Taxol also inhibits chemotaxis in rabbit leukocytes . The results strongly suggest the role of closely linked membrane-cytoskeleton interactions in leukocyte chemotaxis, in which tyrosinolation of tubulin may be functionally involved .Chemotaxis, the directed migration of cells in response to a chemical gradient, has been demonstrated in a variety of cells, including bacteria (1), the cellular slime molds (7, 18), leukocytes (47, 48), fibroblasts (30), and neuronal (36), embryonal (2), and tumor (37) cells. Chemotaxis in general has been shown to be receptor mediated (4,14,21,49), and the activated receptor in stimulated cells is believed to deliver a signal to the motility elements of the cells (such as microfilaments and microtubules), resulting in their orientation and subsequent directional migration towards the chemoattractant (12,13,45) . The evidence for a functional role of microtubules in leukocyte chemotaxis has been somewhat controversial. However, work from several laboratories has suggested that microtubules play an important role in leukocyte chemotaxis (16,22,28) . It was shown that exposure of leukocytes to attractants induces microtubule assembly before locomotion . This assembly was blocked by colchicine, which also prevented their proper orientation toward chemoattractants (9,22,29,32) . These results suggested that microtubules were required for the initial ori-232

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Polymorphonuclear Leukocyte Chemotactic Activity in Rabbit Serum and Guinea Pig Serum Treated with Immune Complexes: Evidence for C5a as the Major Chemotactic Factor

Cited by 148 publications

References 15 publications

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL‐4 and IL‐10

An Anti-C1s Monoclonal, TNT003, Inhibits Complement Activation Induced by Antibodies Against HLA

Stimulation of tubulin tyrosinolation in rabbit leukocytes evoked by the chemoattractant formyl-methionyl-leucyl-phenylalanine.

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