Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity

Mitchell, Leah; Hansen, Ryan J.; Beaupre, Adam J.; Gustafson, Daniel L.; Dow, Steven

doi:10.1016/j.intimp.2012.11.016

Cited by 28 publications

(28 citation statements)

References 26 publications

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“…The systemic administration of RS 504393, a CCR2 antagonist [25], dose dependently inhibits thermal hyperalgesia in mice with either acute or chronic peripheral inflammation. The antihyperalgesic effect evoked by the highest dose assayed of RS 504393 (3 mg/kg) was rather brief reaching its maximum 30 min after administration and completely disappearing in 1 h. However, the repeated administration of this drug every 6 h induced a more maintained antihyperalgesic effect that could rely on its accumulation as previously described with an RS 504393 analog administered with the same schedule [23].…”

Section: Discussionsupporting

confidence: 51%

Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Llorián-Salvador

Pevida

González-Rodríguez

et al. 2016

Fundamemntal Clinical Pharma

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Chemokine CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is a molecule that in addition to its well-established role in chemotaxis can also act as nociceptor sensitizer. The upregulation of this chemokine in inflamed tissues could suggest its involvement in inflammatory hypernociception. Thus, we have measured CCL2 levels in mice with acute or chronic inflammation due to the intraplantar (i.pl.) injection of carrageenan or complete Freund's adjuvant (CFA), respectively, and we have studied whether inflammatory hyperalgesia or allodynia could be attenuated by blocking CCR2 receptors or neutralizing CCL2 with an anti-CCL2 antibody. A remarkable increase in CCL2 concentration was detected by ELISA in paw homogenates coming from carrageenan- or CFA-inflamed mice, being its expression mainly localized in macrophages, as shown by immunohistochemical assays. The s.c. (0.3-3 mg/kg) or i.pl. (0.3-3 μg) administration of the CCR2 antagonist, RS 504393, dose dependently inhibited thermal hyperalgesia measured in acutely or chronically inflamed mice, whereas s.c. administration of this drug did not reduce inflammatory mechanical allodynia. Furthermore, the inhibition of inflammatory hyperalgesia after the administration of an anti-CCL2 antibody (0.1-1 μg; i.pl.) suggests that CCL2 could be the endogenous chemokine responsible for CCR2-mediated hyperalgesic effects. Besides, the acute administration of the highest antihyperalgesic dose of RS 504393 assayed did not reduce paw tumefaction or modify the presence of inflammatory cells. These results indicate that the blockade of the CCL2/CCR2 system can counteract inflammatory hyperalgesia, being this antinociceptive effect unrelated to a decrease in the inflammatory reaction.

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Section: Discussionsupporting

confidence: 51%

Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Llorián-Salvador

Pevida

González-Rodríguez

et al. 2016

Fundamemntal Clinical Pharma

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“…INCB3284 had no effects on systolic BP of WTmice in the absence or presence of 2% saline. Blockade of CCR2 by another CCR2-selective antagonist, 25,26 RS102895, also eliminated HS-induced increase in BP but did decrease it to the level of WT mice (Supplemental Figure 2). These results showed that the CCR2-mediated pathway was involved in salt sensitivity and salt-induced hypertension in KL(+/2) mice but not in spontaneous elevation of BP in KL(+/2) mice.…”

Section: Resultsmentioning

confidence: 95%

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

Zhou

Chen

et al. 2015

Journal of the American Society of Nephrology

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Klotho (KL) is a newly discovered aging suppressor gene. In mice, the KL gene extends the lifespan when overexpressed and shortens the lifespan when disrupted. This study investigated if KL deficiency affects BP and salt sensitivity using KL mutant heterozygous (+/2) mice and wild-type (WT) mice (9 weeks of age, 16 mice per group). Notably, systolic BP in KL(+/2) mice began to increase at the age of 15 weeks, reached a peak level at the age of 17 weeks, and remained elevated thereafter, whereas systolic BP remained consistent in WT mice. High salt (HS) intake further increased BP in KL(+/2) mice but did not affect BP in WT mice. Blockade of CC chemokine receptor 2 (CCR2), involved in monocyte chemotaxis, by a specific CCR2 antagonist (INCB3284) abolished the HS-induced increase in BP in KL(+/2) mice. Furthermore, HS loading substantially increased the expression of monocyte chemotactic protein-1 and the infiltration of macrophages and T cells in kidneys in KL(+/2) mice, and treatment with INCB3284 abolished these effects. Treatment of KL(+/2) mice with INCB3284 also attenuated the increased renal expressions of serum glucocorticoid-regulated kinase 1, thiazide-sensitive NaCl cotransporter, and ATP synthase b along with the renal structural damage and functional impairment induced by HS loading. In conclusion, KL deficiency caused salt-sensitive hypertension and renal damage by CCR2-mediated inflammation. In 1997, a new aging suppressor gene was identified and named after the purported Greek Moira Klotho, 1 who spins the thread of life and controls the ultimate destiny of humans. Insertional mutation of mouse klotho gene resulted in extensive premature aging phenotypes and shortens lifespan. 1 However, overexpression of mouse klotho gene extended the lifespan by 20%-30% and rescued aging disorders. 2 Therefore, klotho is an antiaging gene.Aging is characterized by age-related deterioration in health. Hypertension is a common agingrelated disorder. The prevalence of hypertension increases with age. 3 On the basis of an epidemiologic study, 3 the prevalence of hypertension is more than doubled in the elderly than the young population. More than two thirds of individuals over age 65 years suffer from hypertension according to the Seventh Report of the Joint National Committee. 4 Salt intake is one of the main environmental factors contributing to the development of hypertension. An increase in salt sensitivity has been noted with advancing age in numerous studies. 5-9 Salt sensitivity is more common in the old than the young population. The relationship of age and salt sensitivity seems to be stronger in hypertensive than

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“…injection [16] to female sm-EAN-affected CCR2 WT mice from days 13 to 17 post-induction for a total of 5 days. Apart from establishing functional relevance of CCR2 signaling following clinically apparent disease, these series of studies were designed to mimic a therapeutic drug trial.…”

Section: Methodsmentioning

confidence: 99%

CCR2 Gene Deletion and Pharmacologic Blockade Ameliorate a Severe Murine Experimental Autoimmune Neuritis Model of Guillain-Barré Syndrome

et al. 2014

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The molecular determinants and signaling pathways responsible for hematogenous leukocyte trafficking during peripheral neuroinflammation are incompletely elucidated. Chemokine ligand/receptor pair CCL2/CCR2 has been pathogenically implicated in the acute inflammatory demyelinating polyradiculoneuropathy variant of Guillain-Barré syndrome (GBS). We evaluated the role of CCR2 in peripheral neuroinflammation utilizing a severe murine experimental autoimmune neuritis (sm-EAN) model. Sm-EAN was induced in 8–12 week old female SJL CCR2 knockout (CCR2KO), heterozygote (CCR2HT) and wild type (CCR2WT) mice, and daily neuromuscular severity scores and weights recorded. In vitro and in vivo splenocyte proliferation and cytokine expression assays, and sciatic nerve Toll-like receptor (TLR) 2, TLR4 and CCL2 expression assays were performed to evaluate systemic and local innate immune activation at disease onset. Motor nerve electrophysiology and sciatic nerve histology were also performed to characterize the inflammatory neuropathy at expected peak severity. To further determine the functional relevance of CCR2 in sm-EAN, 20 mg/kg CCR2 antagonist, RS 102895 was administered daily for 5 days to a cohort of CCR2WT mice following sm-EAN disease onset, with efficacy compared to 400 mg/kg human intravenous immunoglobulin (IVIg). CCR2KO mice were relatively resistant to sm-EAN compared to CCR2WT and CCR2HT mice, associated with attenuated peripheral nerve demyelinating neuritis. Partial CCR2 gene deletion did not confer any protection against sm-EAN. CCR2KO mice demonstrated similar splenocyte activation or proliferation profiles, as well as TLR2, TLR4 and CCL2 expression to CCR2WT or CCR2HT mice, implying a direct role for CCR2 in sm-EAN pathogenesis. CCR2 signaling blockade resulted in rapid, near complete recovery from sm-EAN following disease onset. RS 102895 was significantly more efficacious than IVIg. CCR2 mediates pathogenic hematogenous monocyte trafficking into peripheral nerves, with consequential demyelination in sm-EAN. CCR2 is amenable to pharmacologic blockade, making it a plausible drug target for GBS.

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Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity

Cited by 28 publications

References 26 publications

Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Analgesic effects evoked by a CCR2 antagonist or an anti‐CCL2 antibody in inflamed mice

Klotho Gene Deficiency Causes Salt-Sensitive Hypertension via Monocyte Chemotactic Protein-1/CC Chemokine Receptor 2–Mediated Inflammation

CCR2 Gene Deletion and Pharmacologic Blockade Ameliorate a Severe Murine Experimental Autoimmune Neuritis Model of Guillain-Barré Syndrome

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